BRD1 deficiency affects SREBF1-related lipid metabolism through regulating H3K9ac/H3K9me3 transition to inhibit HCC progression.

Abstract

BRD1 encodes a protein containing a bromodomain, which is an essential component of histone acetyltransferase (HAT) complexes. These complexes play a crucial role in the regulation of gene transcription and the modification of chromatin structures. The aberrant expression of BRD1 is frequently observed across a range of cancer types, including hepatocellular carcinomas (HCC). However, the precise mechanisms through which BRD1 contributes to tumorigenesis, especially in HCC, remain unclear. In our investigation, we have uncovered a novel role for BRD1 as an oncogene implicated the regulation of lipid metabolism in HCC progression. Specifically, the deficiency of BRD1 impedes the proliferation and metastasis of HCC cells reducing the accumulation of lipid droplets and cholesterol levels. This effect is mediated through the SREBF1-induced downregulation of SCD1 expression in HCC cells. Mechanistically, the ablation of BRD1 disrupts acetylation level of H3K9, culminating in the subsequent trimethylation of H3K9 (H3K9me3). Notably, the H3K14ac partially colocalizes with H3K9me3 and its methyltransferase SETDB1 to from a double labeling of both H3K14ac and H3K9me3 at the SREBF1 promoter. This double labeling contributes to the creation of a repressive environment, ultimately leading to the downregulation of SREBF1 gene expression in HCC. Furthermore, the combinatorial use of a BRD1 inhibitor and simvastatin augments antitumor efficacy in vivo. Collectively, our findings underscore BRD1 as a critical regulator of SREBF1-associated lipid metabolism and a participant in HCC progression through a distinct epigenetic regulatory mechanism. These discoveries further suggest a promising epigenetic therapeutic approach for the treatment of HCC.