Nuclear KRT19 is a transcriptional corepressor promoting histone deacetylation and liver tumorigenesis

作者：Shixun Han, Haonan Fan, Guoxuan Zhong, Lei Ni, Wenhao Shi, Yushan Fang, Chenliang Wang, Li Wang, Lang Song, Jianhui Zhao, Mei Tang, Bing Yang, Li Li, Xueli Bai, Qi Zhang, Tingbo Liang, Yanhui Xu, Xin‐Hua Feng, Chen Ding, Dong Fang, Bin Zhao · 发表于：Hepatology · 年份：2024 · DOI：10.1097/hep.0000000000000875 · 被引用次数：15 · 研究领域：Skin and Cellular Biology Research、Nuclear Structure and Function、Genomics and Chromatin Dynamics

BACKGROUND AND AIMS: 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. APPROACH AND RESULTS: 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 and REST corepressor 1, components of the corepressor 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 histone deacetylase 1 and REST corepressor 1 interaction, thus increasing 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 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 histone deacetyla...