Histone methylation is a context-dependent modification that regulates gene expression,and the trimethylation of histone H3 lysine 27(H3K27me3)usually induces gene silencing.Overcoming colorectal cancer(CRC)chemoresis...Histone methylation is a context-dependent modification that regulates gene expression,and the trimethylation of histone H3 lysine 27(H3K27me3)usually induces gene silencing.Overcoming colorectal cancer(CRC)chemoresistance is currently a huge challenge,but the relationship between H3K27me3 modification and chemoresistance remains largely unclear.Here,we found that H3K27me3 levels positively correlated with the metastasis-free survival of CRC patients and a low H3K27me3 level predicted a poor outcome upon chemotherapeutic drug treatment.Oxaliplatin stimulation significantly induced the expression of H3K27 lysine demethylase 6A/6B(KDM6A/6B),thus decreasing the level of H3K27me3 in CRC cells.Elevation of H3K27me3 level through KDM6A/6B depletion or GSK-J4(a KDM6A/6B inhibitor)treatment significantly enhanced oxaliplatin-induced apoptosis.Conversely,when inhibiting the expression of H3K27me3 by EPZ-6438,an inhibitor of the histone methyltransferase EZH2,the proportion of apoptotic cells remarkably decreased.In addition,the combination of GSK-J4 and oxaliplatin significantly inhibited tumor growth in an oxaliplatin-resistant patient-derived xenograft model.Importantly,we revealed that oxaliplatin treatment dramatically induced NOTCH2 expression,which was caused by downregulation of H3K27me3 level on the NOTCH2 transcription initiation site.Thus,the activated NOTCH signaling promoted the expression of stemness-related genes,which resulted in oxaliplatin resistance.Furthermore,oxaliplatin-induced NOTCH signaling could be interrupted by GSK-J4 treatment.Collectively,our findings suggest that elevating H3K27me3 level can improve drug sensitivity in CRC patients.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This work was supported by the National Program on Key Research(2018YFA0107500 and 2016YFC1302400)the National Natural Science Foundation of China(91742113 and 31570902)Natural Science Foundation of Shanghai(14ZR14-26300,18ZR1424400,18ZR1446400,and 18431902700).
文摘Histone methylation is a context-dependent modification that regulates gene expression,and the trimethylation of histone H3 lysine 27(H3K27me3)usually induces gene silencing.Overcoming colorectal cancer(CRC)chemoresistance is currently a huge challenge,but the relationship between H3K27me3 modification and chemoresistance remains largely unclear.Here,we found that H3K27me3 levels positively correlated with the metastasis-free survival of CRC patients and a low H3K27me3 level predicted a poor outcome upon chemotherapeutic drug treatment.Oxaliplatin stimulation significantly induced the expression of H3K27 lysine demethylase 6A/6B(KDM6A/6B),thus decreasing the level of H3K27me3 in CRC cells.Elevation of H3K27me3 level through KDM6A/6B depletion or GSK-J4(a KDM6A/6B inhibitor)treatment significantly enhanced oxaliplatin-induced apoptosis.Conversely,when inhibiting the expression of H3K27me3 by EPZ-6438,an inhibitor of the histone methyltransferase EZH2,the proportion of apoptotic cells remarkably decreased.In addition,the combination of GSK-J4 and oxaliplatin significantly inhibited tumor growth in an oxaliplatin-resistant patient-derived xenograft model.Importantly,we revealed that oxaliplatin treatment dramatically induced NOTCH2 expression,which was caused by downregulation of H3K27me3 level on the NOTCH2 transcription initiation site.Thus,the activated NOTCH signaling promoted the expression of stemness-related genes,which resulted in oxaliplatin resistance.Furthermore,oxaliplatin-induced NOTCH signaling could be interrupted by GSK-J4 treatment.Collectively,our findings suggest that elevating H3K27me3 level can improve drug sensitivity in CRC patients.
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.
