P300-dependent acetylation of histone H3 is required for EGFR-mediated HMGA2 transcription in hepatocellular carcinoma

Abstract

<jats:title>Abstract</jats:title> <jats:p>Background High-mobility group protein A2 (HMGA2) is highly expressed in hepatocellular carcinoma cells and contributes to tumor metastasis and poor patient survival. However, the molecular mechanism of HMGA2 transcriptional regulation in hepatocellular carcinoma cells remains largely unclear. Methods Mouse model of lung metastasis was used to evaluate the effects of HMGA2 on hepatocellular carcinoma. DEN-induced rat model of hepatocellular carcinoma was used to measure the expression of HMGA2 and histone H3 acetylation. Immunohistochemistry was used to analyze the expression levels of HMGA2 in 39 matched HCC tissues and adjacent non-tumor tissues. Real-time PCR, Western blotting and Chromatin Immunoprecipitation assay were used to investigate the underlying mechanisms by which HMGA2 overexpression in hepatocellular carcinoma cells. Result Compared with adjacent non-tumour tissues, the expression of HMGA2 was significantly upregulated in human HCC tumor tissues. Moreover, We demonstrated that the expression HMGA2 was upregulated in HCC, and the elevated HMGA2 could promote tumor metastasis. Incubation HCC cells with Epidermal growth factor (EGF) could promote the expression of HMGA2 mRNA and protein. Knockdown of p300 can reverse EGF-induced HMGA2 expression and histone H3-K9 acetylation, while a phosphorylation-mimic p300 S1834D mutant can stimulate HMGA2 expression as well as H3-K9 acetylation in HCC cells. Furthermore, we identified p300-mediated H3-K9 acetylation participates in EGF-induced HMGA2 expression in HCC. In addition, the levels of H3-K9 acetylation positively correlated with the expression levels of HMGA2 in human HCC specimens. Conclusion p300-dependent acetylation of histone H3 is required for EGFR-mediated HMGA2 transcription in hepatocellular carcinoma.</jats:p>