Alcohol consumption contributes to global mortality and cancer development.Acetaldehyde(ACE),the oxidized metabolite of alcohol,is highly reactive towards DNA,resulting in DNA adducts.ACE can be detoxified to acetate ...Alcohol consumption contributes to global mortality and cancer development.Acetaldehyde(ACE),the oxidized metabolite of alcohol,is highly reactive towards DNA,resulting in DNA adducts.ACE can be detoxified to acetate by acetaldehyde dehydrogenase type 2(ALDH2).ALDH2 deficiency can lead to ACE accumulation and DNA damage.展开更多
Wnt/β-catenin signaling plays a critical role in colorectal cancer(CRC)tumorigenesis and the homeostasis of colorectal cancer stem cells(CSCs),but its molecular mechanism remains unclear.B-cell lymphoma 3(Bcl-3),a me...Wnt/β-catenin signaling plays a critical role in colorectal cancer(CRC)tumorigenesis and the homeostasis of colorectal cancer stem cells(CSCs),but its molecular mechanism remains unclear.B-cell lymphoma 3(Bcl-3),a member of the IκB family,is overexpressed in CRC and promotes tumorigenicity.Here,we report a novel function of Bcl-3 in maintaining colorectal CSC homeostasis by activating Wnt/β-catenin signaling.Silencing Bcl-3 suppresses the self-renewal capacity of colorectal CSCs and sensitizes CRC cells to chemotherapeutic drugs through a decrease in Wnt/β-catenin signaling.Moreover,our data show that Bcl-3 is a crucial component of Wnt/β-catenin signaling and is essential forβ-catenin transcriptional activity in CRC cells.Interestingly,Wnt3a increases the level and nuclear translocation of Bcl-3,which binds directly toβ-catenin and enhances the acetylation ofβ-catenin at lysine 49(Ac-K49-β-catenin)and transcriptional activity.Bcl-3 depletion decreases the Ac-K49-β-catenin level by increasing the level of histone deacetylase 1 to remove acetyl groups fromβ-catenin,thus interrupting Wnt/β-catenin activity.In CRC clinical specimens,Bcl-3 expression negatively correlates with the overall survival of CRC patients.A significantly positive correlation was found between the expression of Bcl-3 and Ac-K49-β-catenin.Collectively,our data reveal that Bcl-3 plays a crucial role in CRC chemoresistance and colorectal CSC maintenance via its modulation of the Ac-K49-β-catenin,which serves as a promising therapeutic target for CRC.展开更多
基金supported by grants from the National Nature Science Foundation of China(No.82172565,81620108022,81872245,91129303,991729302,81572759,,31900441,82003069,82103571,882002941,82072570,91129733,81502702).
文摘Alcohol consumption contributes to global mortality and cancer development.Acetaldehyde(ACE),the oxidized metabolite of alcohol,is highly reactive towards DNA,resulting in DNA adducts.ACE can be detoxified to acetate by acetaldehyde dehydrogenase type 2(ALDH2).ALDH2 deficiency can lead to ACE accumulation and DNA damage.
基金funded by the National Program on Key Research(2018YFA0107500,2016YFC1302400)National Basic Research Program(2014CB541904 and 2014CB943600)+3 种基金National Natural Science Foundation of China(91742113,31570902,81702950,81772798,91949102 and 81771752)Natural Science Foundation of Shanghai(14ZR1426300,18ZR1424400,18ZR1446400,18431902700)China Postdoctoral Science Foundation(2017M611633)Guangzhou Key Medical Discipline Construction Project Fund.
文摘Wnt/β-catenin signaling plays a critical role in colorectal cancer(CRC)tumorigenesis and the homeostasis of colorectal cancer stem cells(CSCs),but its molecular mechanism remains unclear.B-cell lymphoma 3(Bcl-3),a member of the IκB family,is overexpressed in CRC and promotes tumorigenicity.Here,we report a novel function of Bcl-3 in maintaining colorectal CSC homeostasis by activating Wnt/β-catenin signaling.Silencing Bcl-3 suppresses the self-renewal capacity of colorectal CSCs and sensitizes CRC cells to chemotherapeutic drugs through a decrease in Wnt/β-catenin signaling.Moreover,our data show that Bcl-3 is a crucial component of Wnt/β-catenin signaling and is essential forβ-catenin transcriptional activity in CRC cells.Interestingly,Wnt3a increases the level and nuclear translocation of Bcl-3,which binds directly toβ-catenin and enhances the acetylation ofβ-catenin at lysine 49(Ac-K49-β-catenin)and transcriptional activity.Bcl-3 depletion decreases the Ac-K49-β-catenin level by increasing the level of histone deacetylase 1 to remove acetyl groups fromβ-catenin,thus interrupting Wnt/β-catenin activity.In CRC clinical specimens,Bcl-3 expression negatively correlates with the overall survival of CRC patients.A significantly positive correlation was found between the expression of Bcl-3 and Ac-K49-β-catenin.Collectively,our data reveal that Bcl-3 plays a crucial role in CRC chemoresistance and colorectal CSC maintenance via its modulation of the Ac-K49-β-catenin,which serves as a promising therapeutic target for CRC.
