Matrix stiffness-induced upregulation of histone acetyltransferase KAT6A promotes hepatocellular carcinoma progression through regulating SOX2 expression

Background Lysine acetyltransferase 6 A (KAT6A) is a MYST-type histone acetyltransferase (HAT) enzyme, which contributes to histone modification and cancer development. However, its biological functions and molecular mechanisms, which respect to hepatocellular carcinoma (HCC), are still largely unknown. Methods Immunohistochemical, western blot and qRT-PCR analysis of KAT6A were performed. A series of in vitro and in vivo experiments were conducted to reveal the role of KAT6A in the progression of HCC. Results We demonstrated that KAT6A expression was upregulated in HCC tissues and cell lines. Clinical analysis showed that increased KAT6A was significantly associated with malignant prognostic features and shorter survival. Gain- and loss-of-function experiments indicated that KAT6A promoted cell viability, proliferation and colony formation of HCC cells in vitro and in vivo. We confirmed that KAT6A acetylates lysine 23 of histone H3 (H3K23), and then enhances the association of the nuclear receptor binding protein TRIM24 and H3K23ac. Consequently, TRIM24 functions as a transcriptional activator to activate SOX2 transcription and expression, leading to HCC tumorigenesis. Restoration of SOX2 at least partially abolished the biological effects of KAT6A on HCC cells. Overexpression of KAT6A acetyltransferase activity-deficient mutants or TRIM24 mutants lacking H3K23ac binding sites did not affect SOX2 expression and HCC biological function. Moreover, matrix stiffness can upregulate the expression of KAT6A in HCC cells. Conclusions Our data support the first evidence that KAT6A plays an oncogenic role in HCC through H3K23ac/TRIM24-SOX2 pathway, and represents a promising therapeutic strategy for HCC patients.

Automated summary

KAT6A is upregulated in hepatocellular carcinoma (HCC) tissues and cell lines and is associated with malignant prognostic features and shorter survival. It acetylates lysine 23 of histone H3 (H3K23), enhances the association between the nuclear receptor binding protein TRIM24 and H3K23ac, and activates the transcription and expression of SOX2, leading to HCC tumorigenesis.