组蛋白
癌变
组蛋白脱乙酰基酶
表观遗传学
癌症研究
化学
细胞生物学
生物化学
癌症
生物
转录因子
基因
遗传学
作者
Shixun Han,Haonan Fan,Guoxuan Zhong,Lei Ni,Wenhao Shi,Yushan Fang,Chenliang Wang,Wenming Wang,Song Liu,Jianhui Zhao,Mei Tang,Bing Yang,Li Li,Xueli Bai,Tingbo Liang,Tingbo Liang,Yanhui Xu,Xin‐Hua Feng,Ding Chen,Fang Dong,Bin Zhao
标识
DOI:10.1097/hep.0000000000000875
摘要
Epigenetic reprogramming and escape from terminal differentiation are poorly understood enabling characteristics of liver cancer. Keratin 19 (KRT19), classically known to form the intermediate filament cytoskeleton, is a marker of stemness and worse prognosis in liver cancer. This study aimed to address the functional roles of KRT19 in liver tumorigenesis and to elucidate the underlying mechanisms.Using multiplexed genome editing of hepatocytes in vivo, we demonstrated that KRT19 promoted liver tumorigenesis in mice. Cell fractionation revealed a previously unrecognized nuclear fraction of KRT19. Tandem affinity purification identified histone deacetylase 1 (HDAC1) and REST co-repressor 1 (RCOR1), components of the co-repressor of RE-1 silencing transcription factor (CoREST) complex as KRT19-interacting proteins. KRT19 knockout markedly enhanced histone acetylation levels. Mechanistically, KRT19 promotes CoREST complex formation by enhancing HDAC1 and RCOR1 interaction, thus increases the deacetylase activity. ChIP-seq revealed hepatocyte-specific genes, such as hepatocyte nuclear factor 4 alpha (HNF4A), as direct targets of KRT19-CoREST. In addition, we identified forkhead box P4 (FOXP4) as a direct activator of aberrant KRT19 expression in liver cancer. Furthermore, treatment of primary liver tumors and patient-derived xenografts in mice suggest that KRT19 expression has the potential to predict response to HDAC inhibitors especially in combination with Lenvatinib.Our data show that nuclear KRT19 acts as a transcriptional co-repressor through promoting the deacetylase activity of the CoREST complex, resulting in dedifferentiation of liver cancer. These findings reveal a previously unrecognized function of KRT19 in directly shaping the epigenetic landscape in cancer.
科研通智能强力驱动
Strongly Powered by AbleSci AI