P300‐dependent acetylation of histone H3 is required for epidermal growth factor receptor‐mediated high‐mobility group protein A2 transcription in hepatocellular carcinoma

Abstract

High‐mobility group protein A2 (HMGA2) is highly expressed in hepatocellular carcinoma (HCC) cells and contributes to tumor metastasis and poor patient survival. However, the molecular mechanism through which HMGA2 is transcriptionally regulated in HCC cells remains largely unclear. Here, we showed that the expression HMGA2 was upregulated in HCC, and that elevated HMGA2 could promote tumor metastasis. Incubation of HCC cells with epidermal growth factor (EGF) could promote the expression of HMGA2 mRNA and protein. Mechanistic studies suggested that EGF can phosphorylate p300 at Ser1834 residue through the PI3K/Akt signaling pathway in HCC cells. Knockdown of p300 can reverse EGF‐induced HMGA2 expression and histone H3‐K9 acetylation, whereas a phosphorylation‐mimic p300 S1834D mutant can stimulate HMGA2 expression as well as H3‐K9 acetylation in HCC cells. Furthermore, we identified that 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 a chemically induced HCC model in rats and human HCC specimens.

Roles and regulation of histone acetylation in hepatocellular carcinoma

“…In addition, histone acetyltransferase p300 and hMOF are involved in inducing HCC migration and vascular invasion by mediating the acetylation of some oncogenes and enhancing their transcriptions ( Niu et al, 2020 ; Pote et al, 2020 ; Liang et al, 2021 ). Epigenetic activation of the microRNAs by histone acetylation also contributes to EMT process and HCC metastasis ( Zhang et al, 2013 ; Wen et al, 2020 ).…”

Clinical implications and biological features of a novel postoperative recurrent HCC classification: A multi‐centre study

“…HMGA2 , which is reputedly critical for embryonic stem cell development, is highly expressed in pluripotent embryonic stem cells during embryogenesis 28 . Liang et al 29 reported that knockdown of HMGA2 reduces the number of lung metastases in tumour‐bearing mice. In the present study, HMGA2 enhanced HCC malignant behaviour, including cell proliferation, anti‐apoptosis, migration/invasion in vitro and tumour growth in vivo.…”

Elevation of spermine remodels immunosuppressive microenvironment through driving the modification of PD-L1 in hepatocellular carcinoma

“…Recently, Li et al found that the activation of epidermal growth factor receptor (EGFR) can inactivate GSK3β and thereby stabilizes PD-L1 expression, accounting for breast cancer cell immunosuppression [ 61 ]. Since hyperactivation of EGFR is frequently observed in hepatocellular carcinoma, which is associated with aggressive tumors and poor survival rates [ 62 , 63 ]. Therefore, it raises the possibility that EGFR/GSK-3β/PD-L1 pathway may suppress T-cell activity in HCC.…”