VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors.Nevertheless,pancreatic adenocarcinoma(PAAD)cells can reinstate tumor angiogenesis via activation of VEGF-indep...VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors.Nevertheless,pancreatic adenocarcinoma(PAAD)cells can reinstate tumor angiogenesis via activation of VEGF-independent pathways,thereby conferring resistance to VEGF inhibitors.Bioinformatic analysis showed that BICC1 was one of the top genes involved in the specific angiogenesis process of PAAD.The analysis of our own cohort confirmed that BICC1 was overexpressed in human PAAD tissues and was correlated to increased microvessel density and tumor growth,and worse prognosis.In cells and mice with xenograft tumors,BICC1 facilitated angiogenesis in pancreatic cancer in a VEGF-independent manner.Mechanistically,as an RNA binding protein,BICC1 bounds to the 3’UTR of Lipocalin-2(LCN2)mRNA and post-transcriptionally up-regulated LCN2 expression in PAAD cells.When its level is elevated,LCN2 binds to its receptor 24p3R,which directly phosphorylates JAK2 and activates JAK2/STAT3 signal,leading to increased production of an angiogenic factor CXCL1.Blocking of the BICC1/LCN2 signalling reduced the microvessel density and tumor volume of PAAD cell grafts in mice,and increased the tumor suppressive effect of gemcitabine.In conclusion,BICC1 plays a pivotal role in the process of VEGF-independent angiogenesis in pancreatic cancer,leading to resistance to VEGF inhibitors.BICC1/LCN2 signaling may serve as a promising anti-angiogenic therapeutic target for pancreatic cancer patients.展开更多
Background:Programmed death ligand 1(PD-L1)has been demonstrated to facilitate tumor progression and therapeutic resistance in an immuneindependent manner.Nevertheless,the function and underlying signaling network(s)o...Background:Programmed death ligand 1(PD-L1)has been demonstrated to facilitate tumor progression and therapeutic resistance in an immuneindependent manner.Nevertheless,the function and underlying signaling network(s)of cancer cell-intrinsic PD-L1 action remain largely unknown.Herein,we sought to better understand how ubiquitin-specific peptidase 51(USP51)/PD-L1/integrin beta-1(ITGB1)signaling performs a cell-intrinsic role in mediating chemotherapeutic resistance in non-small cell lung cancer(NSCLC).Methods:Western blotting and flow cytometry were employed for PD-L1 detection in NSCLC cell lines.Coimmunoprecipitation and pulldown analyses,protein deubiquitination assay,tissue microarray,bioinformatic analysis and molecular biology methods were then used to determine the significance of PD-L1 in NSCLC chemoresistance and associated signaling pathways in several different cell lines,mouse models and patient tissue samples.Ubiquitin-7-amido-4-methylcoumarin(Ub-AMC)-based deubiquitinase activity,cellular thermal shift and surface plasmon resonance(SPR)analyses were performed to investigate the activity of USP51 inhibitors.Results:We provided evidence that cancer cell-intrinsic PD-L1 conferred the development of chemoresistance by directly binding to its membrane-bound receptor ITGB1 in NSCLC.At the molecular level,PD-L1/ITGB1 interaction subsequently activated the nuclear factor-kappa B(NF-κB)axis to elicit poor response to chemotherapy.We further determined USP51 as a bona fide deubiquitinase that targeted the deubiquitination and stabilization of the PD-L1 protein in chemoresistant NSCLC cells.Clinically,we found a significant direct relationship between the USP51,PD-L1 and ITGB1 contents in NSCLC patients with chemoresistant potency.The elevated USP51,PD-L1 and ITGB1 levels were strongly associated with worse patient prognosis.Of note,we identified that a flavonoid compound dihydromyricetin(DHM)acted as a potential USP51 inhibitor and rendered NSCLC cells more sensitive to chemotherapy by targeting USP51-dependent PD-L1 ubiquitination and degradation in vitro and in vivo.Conclusions:Together,our results demonstrated that the USP51/PD-L1/ITGB1 network potentially contributes to the malignant progression and therapeutic resistance in NSCLC.This knowledge is beneficial to the future design of advanced cancer therapy.展开更多
TGF-β-induced factor homeobox 2(TGIF2)is a transcription regulator that plays essential roles in the regulation of development and cell fate decisions.Aberrant expression of TGIF family proteins has been observed in ...TGF-β-induced factor homeobox 2(TGIF2)is a transcription regulator that plays essential roles in the regulation of development and cell fate decisions.Aberrant expression of TGIF family proteins has been observed in several cancers,including ovarian,esophageal,and colorectal cancers.Here,we report that TGIF2 mediates the EGFR–RAS–ERK signaling pathway to enhance the stemness of lung adenocarcinoma(LUAD)cells and,therefore,promote the progression and metastasis of LUAD.We found that high TGIF2 expression was closely correlated with tumor growth,lymph node metastasis,and survival of patients with LUAD.Mice bearing TGIF2-silenced H1299 xenografts developed smaller tumors and fewer lung metastases.Importantly,silencing TGIF2 decreased the cancer stem cell(CSC)-like properties in A549 and H1299 cells.Furthermore,we identified that TGIF2 binding to the OCT4 promoter promotes its expression.In both LUAD cells and in vivo LUAD mouse models,we revealed that EGFR–RAS–ERK signaling phosphorylated TGIF2 and increased its stability,which was important for TGIF2-promoted LUAD stemness since phosphorylation-deficient TGIF2 mutants lost these functions.Thus,our study revealed that an important factor,TGIF2,bridges EGFR signaling to the CSC characteristics of LUAD cells,which can be utilized as an effective target for LUAD therapy.展开更多
Cancer stem cells(CSCs)are a small population of stem cell-like cancer cells that can initiate tumors in vivo,and are the major source of cancer initiation,relapse,and drug resistance.We previously reported that the p...Cancer stem cells(CSCs)are a small population of stem cell-like cancer cells that can initiate tumors in vivo,and are the major source of cancer initiation,relapse,and drug resistance.We previously reported that the p38 MAPK,through its downstream effectors MK2 and HSP27,suppressed CSC properties by downregulating the expression of transcription factors that mediate stemness in non-small-cell lung cancer(NSCLC)cells,and that despite unaltered total expression of total p38 proteins,the levels of activated p38 were reduced in NSCLC tissues.However,the mechanism underlying the reduced levels of activated p38 in NSCLC is unknown.In this study,we identified WIP1,a p38 phosphatase frequently overexpressed in cancer,as a suppressor of p38 in a pathway that regulates CSC properties in NSCLC.Increased WIP1 expression correlated with reduced levels of activated p38,and with increased levels of a CSC marker in NSCLC tissues.Further investigation revealed that WIP1 promoted stemness-related protein expression and CSC properties by inhibiting p38 activity in NSCLC cells.WIP1 inhibitors are currently under development as anticancer drugs based on their ability to reactivate p53.We found that a WIP1 inhibitor suppressed stemness-related protein expression and CSC properties by activating p38 in NSCLC cells in vitro and in vivo.These studies have identified the WIP1–p38–MK2–HSP27 cascade as a novel signaling pathway that,when altered,promotes CSC properties in NSCLC development,and have defined novel mechanisms underlying the oncogenic activity of WIP1 and the anticancer efficacy of WIP1 inhibitors.展开更多
Metastases are the main cause of cancer-related mortality in breast cancer.Although significant progress has been made in the field of tumor metastasis,the exact molecular mechanisms involved in tumor metastasis are s...Metastases are the main cause of cancer-related mortality in breast cancer.Although significant progress has been made in the field of tumor metastasis,the exact molecular mechanisms involved in tumor metastasis are still unclear.Here,we report that ATOH8-V1,a novel isoform of ATOH8,is highly expressed in breast cancer and is a negative prognostic indicator of survival for patients.Forced expression of ATOH8-V1 dramatically enhances,while silencing of ATOH8-V1 decreases the metastasis of breast cancer cell lines.Moreover,ATOH8-V1 directly binds to the RhoC promoter and stimulates the expression of RhoC,which in turn enhances the metastasis of breast cancer.Altogether,our data demonstrate that ATOH8-V1 is a novel pro-metastatic factor that enhances cancer metastasis,suggesting that AT0H8-V1 is a potential therapeutic target for treatment of metastatic cancers.展开更多
Deregulated telomere length is a causative factor in many physiological and pathological processes,including aging and cancer.Many studies focusing on telomeres have revealed important roles for cooperation between th...Deregulated telomere length is a causative factor in many physiological and pathological processes,including aging and cancer.Many studies focusing on telomeres have revealed important roles for cooperation between the Shelterin protein complex and telomerase in maintaining telomere length.However,it remains largely unknown whether and how aging-related stresses,such as deregulated protein homeostasis,impact telomere length.Here,we explored the possible roles of aminoacyl tRNA synthetases(AARSs),key enzymes catalyzing the first reactions in protein synthesis,in regulating telomere length and aging.We selected seryl tRNA synthetase(SerRS)since our previous studies discovered expanded functions of SerRS in the nucleus in addition to its canonical cytoplasmic role in protein synthesis.In this study,we revealed that overexpression of SerRS promoted cellular senescence and inhibited the growth of cervical tumor xenografts in mice by triggering the senescence of tumor cells.In the nucleus,SerRS directly bound to telomeric DNA repeats and tethered more POT1 proteins to telomeres through a direct interaction between the UNE-S domain of SerRS and the OB1 domain of POT1.We further demonstrated that SerRS-induced enrichment of POT1 prevented the recruitment of telomerase to telomeres,resulting in progressive telomere shortening.Our data suggested a possible molecular link between protein synthesis and telomere length control,the deregulation of which may be associated with aging and cancer.展开更多
Tumor metastasis is the most common cause of cancer-related deaths,yet it remains poorly understood.The transcription factor zinc-finger E-box binding homeobox 1(ZEB1)is involved in the epithelial-to-mesenchymal trans...Tumor metastasis is the most common cause of cancer-related deaths,yet it remains poorly understood.The transcription factor zinc-finger E-box binding homeobox 1(ZEB1)is involved in the epithelial-to-mesenchymal transition(EMT)and plays a pivotal role in tumor metastasis.However,the underlying mechanisms of the posttranslational modification of ZEB1 remain largely unknown.Herein,we demonstrated that specific inhibition of CDK4/6 was able to block tumor metastasis of breast cancer by destabilizing the ZEB1 protein in vitro and in vivo.Mechanistically,we determined that the deubiquitinase USP51 is a bona fide target of CDK4/6.The phosphorylation and activation of USP51 by CDK4/6 is necessary to deubiquitinate and stabilize ZEB1.Moreover,we found a strong positive correlation between the expression of p-RB(an indicator of CDK4/6 activity),p-USP51 and ZEB1 in metastatic human breast cancer samples.Notably,the high expression of p-RB,p-USP51,and ZEB1 was significantly correlated with a poor clinical outcome.Taken together,our results provide evidence that the CDK4/6-USP51-ZEB1 axis plays a key role in breast cancer metastasis and could be a viable therapeutic target for the treatment of advanced human cancers.展开更多
TIFA,also called T2BP,was first identified using yeast two-hybrid screening.Our previous work showed that TIFA suppresses hepatocellular carcinoma(HCC)progression via apoptosis and cell cycle arrest.However,the mechan...TIFA,also called T2BP,was first identified using yeast two-hybrid screening.Our previous work showed that TIFA suppresses hepatocellular carcinoma(HCC)progression via apoptosis and cell cycle arrest.However,the mechanism by which this TIFA suppression occurs remains unclear.Here we demonstrated that TIFA-induced apoptosis demonstrates two distinct time patterns(i.e.,at 48 h and 47 days)when TIFA reconstitution occurs.Moreover,we found that MALT1(a competitor of TIFA)plays a crucial role in short-duration TIFA reconstitution.In this regard,MALT1 silencing with shRNA markedly enhances TIFA-induced apoptosis in vitro and in vivo.In addition,TIFA overexpression triggers JNK and p38 activation in long-duration TIFA reconstitution through TRAF6 binding.In particular,JNK activation leads to TIFA-induced apoptosis while p38 activation governs TIFA-induced cell cycle arrest by p53-p21 signaling in vitro and in vivo.Our data suggest a novel mechanism by which TIFA suppresses HCC progression via both MALT1-dependent and MALT1-independent signaling pathways.This may provide insights into a novel targets where HCC progression may be vulnerable to clinical treatment.展开更多
In eukaryotic cells,DNA damage triggers activation of checkpoint signaling pathways that coordinate cell cycle arrest and repair of damaged DNA.These DNA damage responses serve to maintain genome stability and prevent...In eukaryotic cells,DNA damage triggers activation of checkpoint signaling pathways that coordinate cell cycle arrest and repair of damaged DNA.These DNA damage responses serve to maintain genome stability and prevent accumulation of genetic mutations and development of cancer.The p38 MAPK was previously implicated in cellular responses to several types of DNA damage.However,the role of each of the four p38 isoforms and the mechanism for their involvement in DNA damage responses remained poorly understood.In this study,we demonstrate that p38γ,but not the other p38 isoforms,contributes to the survival of UV-treated cells.Deletion of p38γsensitizes cells to UV exposure,accompanied by prolonged S phase cell cycle arrest and increased rate of apoptosis.Further investigation reveal that p38γis essential for the optimal activation of the checkpoint signaling caused by UV,and for the efficient repair of UVinduced DNA damage.These findings have established a novel role of p38γin UV-induced DNA damage responses,and suggested that p38γcontributes to the ability of cells to cope with UV exposure by regulating the checkpoint signaling pathways and the repair of damaged DNA.展开更多
Recently,in the process of collating the raw data,the authors noticed two inadvertent mistakes in Fig.1 that need to be corrected.1 The correct data are provided as follows.The key findings of the article are not affe...Recently,in the process of collating the raw data,the authors noticed two inadvertent mistakes in Fig.1 that need to be corrected.1 The correct data are provided as follows.The key findings of the article are not affected by these corrections.展开更多
基金National Natural Science Foundation of China(grants 82272680,82072659,81871978,81772633,82272799,81720108028,81525021,81502067,81302082,81272685,31301151,81172355,31471340,31470957,81472264,and 81401957)National Key R&D Program of China(grants 2020YFA0803704)+1 种基金Tianjin Science Foundation for Distinguished Young Scholars(grants 19JCJQJC63100)NIH grant R01CA233844,R01CA256911(to S.Y.).
文摘VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors.Nevertheless,pancreatic adenocarcinoma(PAAD)cells can reinstate tumor angiogenesis via activation of VEGF-independent pathways,thereby conferring resistance to VEGF inhibitors.Bioinformatic analysis showed that BICC1 was one of the top genes involved in the specific angiogenesis process of PAAD.The analysis of our own cohort confirmed that BICC1 was overexpressed in human PAAD tissues and was correlated to increased microvessel density and tumor growth,and worse prognosis.In cells and mice with xenograft tumors,BICC1 facilitated angiogenesis in pancreatic cancer in a VEGF-independent manner.Mechanistically,as an RNA binding protein,BICC1 bounds to the 3’UTR of Lipocalin-2(LCN2)mRNA and post-transcriptionally up-regulated LCN2 expression in PAAD cells.When its level is elevated,LCN2 binds to its receptor 24p3R,which directly phosphorylates JAK2 and activates JAK2/STAT3 signal,leading to increased production of an angiogenic factor CXCL1.Blocking of the BICC1/LCN2 signalling reduced the microvessel density and tumor volume of PAAD cell grafts in mice,and increased the tumor suppressive effect of gemcitabine.In conclusion,BICC1 plays a pivotal role in the process of VEGF-independent angiogenesis in pancreatic cancer,leading to resistance to VEGF inhibitors.BICC1/LCN2 signaling may serve as a promising anti-angiogenic therapeutic target for pancreatic cancer patients.
基金International Science and Technology Cooperation Project of China,Grant/Award Number:2022YFE0133300National Natural Science Foundation of China,Grant/Award Numbers:82172801,81972454。
文摘Background:Programmed death ligand 1(PD-L1)has been demonstrated to facilitate tumor progression and therapeutic resistance in an immuneindependent manner.Nevertheless,the function and underlying signaling network(s)of cancer cell-intrinsic PD-L1 action remain largely unknown.Herein,we sought to better understand how ubiquitin-specific peptidase 51(USP51)/PD-L1/integrin beta-1(ITGB1)signaling performs a cell-intrinsic role in mediating chemotherapeutic resistance in non-small cell lung cancer(NSCLC).Methods:Western blotting and flow cytometry were employed for PD-L1 detection in NSCLC cell lines.Coimmunoprecipitation and pulldown analyses,protein deubiquitination assay,tissue microarray,bioinformatic analysis and molecular biology methods were then used to determine the significance of PD-L1 in NSCLC chemoresistance and associated signaling pathways in several different cell lines,mouse models and patient tissue samples.Ubiquitin-7-amido-4-methylcoumarin(Ub-AMC)-based deubiquitinase activity,cellular thermal shift and surface plasmon resonance(SPR)analyses were performed to investigate the activity of USP51 inhibitors.Results:We provided evidence that cancer cell-intrinsic PD-L1 conferred the development of chemoresistance by directly binding to its membrane-bound receptor ITGB1 in NSCLC.At the molecular level,PD-L1/ITGB1 interaction subsequently activated the nuclear factor-kappa B(NF-κB)axis to elicit poor response to chemotherapy.We further determined USP51 as a bona fide deubiquitinase that targeted the deubiquitination and stabilization of the PD-L1 protein in chemoresistant NSCLC cells.Clinically,we found a significant direct relationship between the USP51,PD-L1 and ITGB1 contents in NSCLC patients with chemoresistant potency.The elevated USP51,PD-L1 and ITGB1 levels were strongly associated with worse patient prognosis.Of note,we identified that a flavonoid compound dihydromyricetin(DHM)acted as a potential USP51 inhibitor and rendered NSCLC cells more sensitive to chemotherapy by targeting USP51-dependent PD-L1 ubiquitination and degradation in vitro and in vivo.Conclusions:Together,our results demonstrated that the USP51/PD-L1/ITGB1 network potentially contributes to the malignant progression and therapeutic resistance in NSCLC.This knowledge is beneficial to the future design of advanced cancer therapy.
基金This work was supported by the National Natural Science Foundation of China(No.81772974 to Y.Shi,No.1672914 to Y.Luo,and No.81972795 to C.Chen).
文摘TGF-β-induced factor homeobox 2(TGIF2)is a transcription regulator that plays essential roles in the regulation of development and cell fate decisions.Aberrant expression of TGIF family proteins has been observed in several cancers,including ovarian,esophageal,and colorectal cancers.Here,we report that TGIF2 mediates the EGFR–RAS–ERK signaling pathway to enhance the stemness of lung adenocarcinoma(LUAD)cells and,therefore,promote the progression and metastasis of LUAD.We found that high TGIF2 expression was closely correlated with tumor growth,lymph node metastasis,and survival of patients with LUAD.Mice bearing TGIF2-silenced H1299 xenografts developed smaller tumors and fewer lung metastases.Importantly,silencing TGIF2 decreased the cancer stem cell(CSC)-like properties in A549 and H1299 cells.Furthermore,we identified that TGIF2 binding to the OCT4 promoter promotes its expression.In both LUAD cells and in vivo LUAD mouse models,we revealed that EGFR–RAS–ERK signaling phosphorylated TGIF2 and increased its stability,which was important for TGIF2-promoted LUAD stemness since phosphorylation-deficient TGIF2 mutants lost these functions.Thus,our study revealed that an important factor,TGIF2,bridges EGFR signaling to the CSC characteristics of LUAD cells,which can be utilized as an effective target for LUAD therapy.
基金supported by NIH/NCI grants(CA131231,CA172115,P30CA012197 to P.S.)the National Key Research and Development Program of China(2018YFE0114300 to R.X.)the National Natural Science Foundation of China(No.81972454(S.Y.),81972882(R.X.)).P.S.is supported by the Anderson Oncology Research Professorship.
文摘Cancer stem cells(CSCs)are a small population of stem cell-like cancer cells that can initiate tumors in vivo,and are the major source of cancer initiation,relapse,and drug resistance.We previously reported that the p38 MAPK,through its downstream effectors MK2 and HSP27,suppressed CSC properties by downregulating the expression of transcription factors that mediate stemness in non-small-cell lung cancer(NSCLC)cells,and that despite unaltered total expression of total p38 proteins,the levels of activated p38 were reduced in NSCLC tissues.However,the mechanism underlying the reduced levels of activated p38 in NSCLC is unknown.In this study,we identified WIP1,a p38 phosphatase frequently overexpressed in cancer,as a suppressor of p38 in a pathway that regulates CSC properties in NSCLC.Increased WIP1 expression correlated with reduced levels of activated p38,and with increased levels of a CSC marker in NSCLC tissues.Further investigation revealed that WIP1 promoted stemness-related protein expression and CSC properties by inhibiting p38 activity in NSCLC cells.WIP1 inhibitors are currently under development as anticancer drugs based on their ability to reactivate p53.We found that a WIP1 inhibitor suppressed stemness-related protein expression and CSC properties by activating p38 in NSCLC cells in vitro and in vivo.These studies have identified the WIP1–p38–MK2–HSP27 cascade as a novel signaling pathway that,when altered,promotes CSC properties in NSCLC development,and have defined novel mechanisms underlying the oncogenic activity of WIP1 and the anticancer efficacy of WIP1 inhibitors.
基金This work was supported by the National Science Foundation for Young Scientists of China(81702994)International S&T Cooperation Program of China(2015DFA30420)We thank Dr Ralph A.Reisfeld from the Scripps Research In stitute for his valuable suggestions and for proof-readi ng this manuscript.
文摘Metastases are the main cause of cancer-related mortality in breast cancer.Although significant progress has been made in the field of tumor metastasis,the exact molecular mechanisms involved in tumor metastasis are still unclear.Here,we report that ATOH8-V1,a novel isoform of ATOH8,is highly expressed in breast cancer and is a negative prognostic indicator of survival for patients.Forced expression of ATOH8-V1 dramatically enhances,while silencing of ATOH8-V1 decreases the metastasis of breast cancer cell lines.Moreover,ATOH8-V1 directly binds to the RhoC promoter and stimulates the expression of RhoC,which in turn enhances the metastasis of breast cancer.Altogether,our data demonstrate that ATOH8-V1 is a novel pro-metastatic factor that enhances cancer metastasis,suggesting that AT0H8-V1 is a potential therapeutic target for treatment of metastatic cancers.
基金This work was supported by grants from the National Natural Science Foundation of China(No.81772974)the Natural Science Foundation of Tianjin City(18JCQNJC12600)+1 种基金the Project of Science and Technology Assistance in Developing Countries(KY201501006)the Ph.D.Candidate Research Innovation Fund of Nankai University.
文摘Deregulated telomere length is a causative factor in many physiological and pathological processes,including aging and cancer.Many studies focusing on telomeres have revealed important roles for cooperation between the Shelterin protein complex and telomerase in maintaining telomere length.However,it remains largely unknown whether and how aging-related stresses,such as deregulated protein homeostasis,impact telomere length.Here,we explored the possible roles of aminoacyl tRNA synthetases(AARSs),key enzymes catalyzing the first reactions in protein synthesis,in regulating telomere length and aging.We selected seryl tRNA synthetase(SerRS)since our previous studies discovered expanded functions of SerRS in the nucleus in addition to its canonical cytoplasmic role in protein synthesis.In this study,we revealed that overexpression of SerRS promoted cellular senescence and inhibited the growth of cervical tumor xenografts in mice by triggering the senescence of tumor cells.In the nucleus,SerRS directly bound to telomeric DNA repeats and tethered more POT1 proteins to telomeres through a direct interaction between the UNE-S domain of SerRS and the OB1 domain of POT1.We further demonstrated that SerRS-induced enrichment of POT1 prevented the recruitment of telomerase to telomeres,resulting in progressive telomere shortening.Our data suggested a possible molecular link between protein synthesis and telomere length control,the deregulation of which may be associated with aging and cancer.
基金supported by grants from the National Natural Science Foundation of China(No.81972454No.81472545+1 种基金and No.81670600)the Tianjin Natural Science Foundation(No.17JCZDJC36600).
文摘Tumor metastasis is the most common cause of cancer-related deaths,yet it remains poorly understood.The transcription factor zinc-finger E-box binding homeobox 1(ZEB1)is involved in the epithelial-to-mesenchymal transition(EMT)and plays a pivotal role in tumor metastasis.However,the underlying mechanisms of the posttranslational modification of ZEB1 remain largely unknown.Herein,we demonstrated that specific inhibition of CDK4/6 was able to block tumor metastasis of breast cancer by destabilizing the ZEB1 protein in vitro and in vivo.Mechanistically,we determined that the deubiquitinase USP51 is a bona fide target of CDK4/6.The phosphorylation and activation of USP51 by CDK4/6 is necessary to deubiquitinate and stabilize ZEB1.Moreover,we found a strong positive correlation between the expression of p-RB(an indicator of CDK4/6 activity),p-USP51 and ZEB1 in metastatic human breast cancer samples.Notably,the high expression of p-RB,p-USP51,and ZEB1 was significantly correlated with a poor clinical outcome.Taken together,our results provide evidence that the CDK4/6-USP51-ZEB1 axis plays a key role in breast cancer metastasis and could be a viable therapeutic target for the treatment of advanced human cancers.
基金This project is supported by the National Basic Research Program(973)of China(No.2013CB967202)the National Natural Science Foundation of China(No.81273331)+2 种基金the National Natural Science Foundation of China(No.81470354)National Natural Science Foundation of China(81301856NL).
文摘TIFA,also called T2BP,was first identified using yeast two-hybrid screening.Our previous work showed that TIFA suppresses hepatocellular carcinoma(HCC)progression via apoptosis and cell cycle arrest.However,the mechanism by which this TIFA suppression occurs remains unclear.Here we demonstrated that TIFA-induced apoptosis demonstrates two distinct time patterns(i.e.,at 48 h and 47 days)when TIFA reconstitution occurs.Moreover,we found that MALT1(a competitor of TIFA)plays a crucial role in short-duration TIFA reconstitution.In this regard,MALT1 silencing with shRNA markedly enhances TIFA-induced apoptosis in vitro and in vivo.In addition,TIFA overexpression triggers JNK and p38 activation in long-duration TIFA reconstitution through TRAF6 binding.In particular,JNK activation leads to TIFA-induced apoptosis while p38 activation governs TIFA-induced cell cycle arrest by p53-p21 signaling in vitro and in vivo.Our data suggest a novel mechanism by which TIFA suppresses HCC progression via both MALT1-dependent and MALT1-independent signaling pathways.This may provide insights into a novel targets where HCC progression may be vulnerable to clinical treatment.
基金This work is supported by grants from National Institute of Health,USA(CA106768,CA131231 and RR025744 to P.S.,AI041637 and AI068896 to J.H.,and CA102361 and CA140972 to XW)an international collaborative grant from National Science Foundation in China(30828019 to P.S.and J.H.).The Scripps manuscript number is 20721.
文摘In eukaryotic cells,DNA damage triggers activation of checkpoint signaling pathways that coordinate cell cycle arrest and repair of damaged DNA.These DNA damage responses serve to maintain genome stability and prevent accumulation of genetic mutations and development of cancer.The p38 MAPK was previously implicated in cellular responses to several types of DNA damage.However,the role of each of the four p38 isoforms and the mechanism for their involvement in DNA damage responses remained poorly understood.In this study,we demonstrate that p38γ,but not the other p38 isoforms,contributes to the survival of UV-treated cells.Deletion of p38γsensitizes cells to UV exposure,accompanied by prolonged S phase cell cycle arrest and increased rate of apoptosis.Further investigation reveal that p38γis essential for the optimal activation of the checkpoint signaling caused by UV,and for the efficient repair of UVinduced DNA damage.These findings have established a novel role of p38γin UV-induced DNA damage responses,and suggested that p38γcontributes to the ability of cells to cope with UV exposure by regulating the checkpoint signaling pathways and the repair of damaged DNA.
文摘Recently,in the process of collating the raw data,the authors noticed two inadvertent mistakes in Fig.1 that need to be corrected.1 The correct data are provided as follows.The key findings of the article are not affected by these corrections.
