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Keratin 19 is a component of CoREST linking transcriptional and epigenetic dysregulation in liver cancer

ABSTRACT: Poor differentiation in cancer is often correlated with higher malignancy and treatment resistance. Dysregulated epigenetic modifications, such as histone acetylation levels, plays a key role in tumor differentiation, and serves as potential targets for treatment. In this report, through screening of transcription factors abnormally activated in HCC, we identified FOXP4, which promotes tumorigenesis through transactivation of KRT19. Remarkably, beyond a marker of stemness, KRT19 actively represses histone acetylation levels, resulting in transcriptional inhibition of differentiation regulators, such as HNF4A, thus promotes tumor malignancy. Mechanistically, KRT19 activates HDAC1 deacetylase by promoting assembly of the CoREST complex in the nucleus. Finally, HDAC inhibitor alone or in combination with lenvatinib specifically suppresses KRT19 and FOXP4 positive human and mouse liver tumors. These findings revealed transcriptional activation of a conditional component for histone deacetylase complex as a mechanism for modulation of epigenetic landscape in cancer, and unveils a new opportunity for targeted therapy.

ORGANISM(S): Mus Musculus

SUBMITTER: Bin Zhao

PROVIDER: PXD044011 | iProX | Sat Jul 22 00:00:00 BST 2023

REPOSITORIES: iProX

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