Radiotherapy is widely used in the management of advanced colorectal cancer(CRC).However,the clinical efficacy is limited by the safe irradiated dose.Sensitizing tumor cells to radiotherapy via interrupting DNA repair...Radiotherapy is widely used in the management of advanced colorectal cancer(CRC).However,the clinical efficacy is limited by the safe irradiated dose.Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation.The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination(HR)DSB repair,and its functions may be affected by HERC2 or BAP1.Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes;however,the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn’t been defined.Through activity-based profiling,we identified PT33 as an active entity for HR repair suppression.Subsequently,we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen.Mechanistically,pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction,interrupting HR repair.Consequently,PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo.Overall,these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.展开更多
Additional sex combs-like 1(ASXL1)interacts with BRCA1-associated protein 1(BAP1)deubiquitinase to oppose the polycomb repressive complex 1(PRC1)-mediated histone H2A ubiquitylation.Germline BAP1 mutations are found i...Additional sex combs-like 1(ASXL1)interacts with BRCA1-associated protein 1(BAP1)deubiquitinase to oppose the polycomb repressive complex 1(PRC1)-mediated histone H2A ubiquitylation.Germline BAP1 mutations are found in a spectrum of human malignancies,while ASXL1 mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis.Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region,resulting in the production of C-terminally truncated mutant ASXL1 proteins.How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogen-esis are unclear.Here,we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes.We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells,and lose the ability to interact with FOXK1/K2.Specific deletion of the mutant allele eliminates the expression of C-termi-nally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1,thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes,particularly those involved in glucose metabolism,oxygen sensing,and JAK-STAT3 signaling pathways.In addition to FOXK1/K2,we also identify other DNA-bind-ing transcription regulators including transcription factors(TFs)which interact with wild-type ASXL1,but not C-terminally truncated mutant.Our results suggest that ASXL1 mutations result in neomorphic alleles that contribute to leukemogenesis at least in part through dominantly inhibiting the wild-type ASXL1 from interacting with BAP1 and thereby impairing the function of ASXL1-BAP1-TF in regulating target genes and leukemia cell growth.展开更多
BACKGROUND Pancreatic cancer(PC)is a leading cause of cancer-related death,given its poor prognosis and the limited benefits of traditional therapies.As tumors become more genetically disorganized as they progress,gen...BACKGROUND Pancreatic cancer(PC)is a leading cause of cancer-related death,given its poor prognosis and the limited benefits of traditional therapies.As tumors become more genetically disorganized as they progress,genetic mutations might become new markers for us to predict their behavior.Nowadays,many inhibitors can selectively target gene products as a form of targeted therapy,with some showing promise as treatment for various types of cancer.CASE SUMMARY We describe a rare case of a PC patient with long-term survival of more than 8 yr.The patient was diagnosed with pancreatic ductal adenocarcinoma(PDAC)with BAP1 and PIK3CA gene mutations and Raf1 fusion and achieved partial response twice after treatment with apatinib in combination with chemotherapy.CONCLUSION BAP1,PIK3CA mutations,and Raf1 fusion are rare in PDAC.Patients with these three gene alterations of PDAC may achieve long-term survival with apatinib.Further research in other contexts is needed to determine whether apatinib has ideal efficacy for PC treatment.展开更多
The release and nuclear translocation of the intracellular domain of Notch receptor(NICD)is the prerequisite for Notch signaling-mediated transcriptional activation.NICD is subjected to various posttranslational modif...The release and nuclear translocation of the intracellular domain of Notch receptor(NICD)is the prerequisite for Notch signaling-mediated transcriptional activation.NICD is subjected to various posttranslational modifications including ubiquitination.Here,we surprisingly found that NUMB proteins stabilize the intracellular domain of NOTCH1 receptor(N1ICD)by regulating the ubiquitin–proteasome machinery,which is independent of NUMB’s role in modulating endocytosis.BAP1,a deubiquitinating enzyme(DUB),was further identified as a positive N1ICD regulator,and NUMB facilitates the association between N1ICD and BAP1 to stabilize N1ICD.Intriguingly,BAP1 stabilizes N1ICD independent of its DUB activity but relying on the BRCA1-inhibiting function.BAP1 strengthens Notch signaling and maintains stem-like properties of cortical neural progenitor cells.Thus,NUMB enhances Notch signaling by regulating the ubiquitinating activity of the BAP1–BRCA1 complex.展开更多
基金supported by the National Natural Science Foundation of China(NSFC)(No.82272743 to Xin Yue(82172812)of NSFC to Ran-yi Liu+4 种基金81871996 to Ran-yi Liu82003218 to Xuecen Wang82072029 to Zhenwei Peng and 81973174 to Xianzhang Bu)Guangdong Basic and Applied Basic Research Foundation(No.2021A1515012496 to Xin Yue and 2022A1515012221 to Xianzhang Bu)Basic Scientific Research Operation of Sun Yat-sen University(No.19ykpy192 to Xin Yue)。
文摘Radiotherapy is widely used in the management of advanced colorectal cancer(CRC).However,the clinical efficacy is limited by the safe irradiated dose.Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation.The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination(HR)DSB repair,and its functions may be affected by HERC2 or BAP1.Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes;however,the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn’t been defined.Through activity-based profiling,we identified PT33 as an active entity for HR repair suppression.Subsequently,we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen.Mechanistically,pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction,interrupting HR repair.Consequently,PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo.Overall,these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.
基金the National Key R&D Program of China(No.2016YFA0501800 to D.Y.2016YFC1303303 to C.Y.)+5 种基金the NSFC Grant(No.31871431 and No.31821002 to D.Y.81572761,81772655 and 81972646 to Y.T.)the Innovative Research Team of High-Level Local Universities in Shanghai(to D.Y.)the Recruitment Program of Global Experts of China(Y.T.)the Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institutions of Higher Learning(V.T.)Shanghai Rising-Star Program(Y.T.).
文摘Additional sex combs-like 1(ASXL1)interacts with BRCA1-associated protein 1(BAP1)deubiquitinase to oppose the polycomb repressive complex 1(PRC1)-mediated histone H2A ubiquitylation.Germline BAP1 mutations are found in a spectrum of human malignancies,while ASXL1 mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis.Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region,resulting in the production of C-terminally truncated mutant ASXL1 proteins.How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogen-esis are unclear.Here,we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes.We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells,and lose the ability to interact with FOXK1/K2.Specific deletion of the mutant allele eliminates the expression of C-termi-nally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1,thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes,particularly those involved in glucose metabolism,oxygen sensing,and JAK-STAT3 signaling pathways.In addition to FOXK1/K2,we also identify other DNA-bind-ing transcription regulators including transcription factors(TFs)which interact with wild-type ASXL1,but not C-terminally truncated mutant.Our results suggest that ASXL1 mutations result in neomorphic alleles that contribute to leukemogenesis at least in part through dominantly inhibiting the wild-type ASXL1 from interacting with BAP1 and thereby impairing the function of ASXL1-BAP1-TF in regulating target genes and leukemia cell growth.
基金Supported by Wu Jieping Medical Foundation,No.320.6750.2020-10-95Sanming Project of Medicine in Shenzhen,No.SZSM202011010.
文摘BACKGROUND Pancreatic cancer(PC)is a leading cause of cancer-related death,given its poor prognosis and the limited benefits of traditional therapies.As tumors become more genetically disorganized as they progress,genetic mutations might become new markers for us to predict their behavior.Nowadays,many inhibitors can selectively target gene products as a form of targeted therapy,with some showing promise as treatment for various types of cancer.CASE SUMMARY We describe a rare case of a PC patient with long-term survival of more than 8 yr.The patient was diagnosed with pancreatic ductal adenocarcinoma(PDAC)with BAP1 and PIK3CA gene mutations and Raf1 fusion and achieved partial response twice after treatment with apatinib in combination with chemotherapy.CONCLUSION BAP1,PIK3CA mutations,and Raf1 fusion are rare in PDAC.Patients with these three gene alterations of PDAC may achieve long-term survival with apatinib.Further research in other contexts is needed to determine whether apatinib has ideal efficacy for PC treatment.
基金supported by grants from the National Key R&D Program of China(2018YFA0800700)the National Natural Science Foundation of China(31671418,31970676,31970770,and 31471361)+3 种基金Hubei Natural Science Foundation(2018CFA016)Fundamental Research Funds for the Central Universities(2042017kf0242)Medical Science Advancement Program(Basic Medical Sciences)of Wuhan University(TFJC2018005)Wuhan University Experiment Technology Project Funding(WHU-2018-SYJS-01).
文摘The release and nuclear translocation of the intracellular domain of Notch receptor(NICD)is the prerequisite for Notch signaling-mediated transcriptional activation.NICD is subjected to various posttranslational modifications including ubiquitination.Here,we surprisingly found that NUMB proteins stabilize the intracellular domain of NOTCH1 receptor(N1ICD)by regulating the ubiquitin–proteasome machinery,which is independent of NUMB’s role in modulating endocytosis.BAP1,a deubiquitinating enzyme(DUB),was further identified as a positive N1ICD regulator,and NUMB facilitates the association between N1ICD and BAP1 to stabilize N1ICD.Intriguingly,BAP1 stabilizes N1ICD independent of its DUB activity but relying on the BRCA1-inhibiting function.BAP1 strengthens Notch signaling and maintains stem-like properties of cortical neural progenitor cells.Thus,NUMB enhances Notch signaling by regulating the ubiquitinating activity of the BAP1–BRCA1 complex.
