Abstract 3681: c-MAF-driven metabolic reprogramming mediates H3K27 hyperacetylation to regulate super enhancer-associated genes

Abstract

Abstract Overexpression of transcription factor c-MAF is found in about 50% of multiple myeloma cases, and associated with the prognostically unfavorable t(14;16) translocation subtype. Genetic alterations can modify the epigenome through metabolite availability that act as substrates in histone modifications, but how this translates into specificities in gene regulation is unclear. Here, we report a novel involvement of c-MAF in metabolically-driven histone acetylation, including the superenhancer mark H3K27ac, through altering acetyl-CoA metabolism. To sustain high levels of acetylation, c-MAF acquired the metabolic flexibility to utilize glutamine in addition to glucose, feeding into the tricarboxylic acid (TCA) cycle as acetyl-CoA sources. Loss-of-function studies indicated that c-MAF is important for citrate-derived acetyl-CoA and H3K27ac levels through metabolic enzymes citrate synthase (CS) and ATP-citrate lyase (ACLY). Furthermore, blocking citrate export from mitochondrial via CRISPR/Cas9 targeting of SLC25A1 reproduced the reductions in H3K27ac. Silencing of c-MAF also displayed defective mitochondrial oxidative phosphorylation attributed to reduced metabolic flux through TCA cycle and downregulation of electron transport chain complex I/II expression, without affecting mitochondrial DNA content. To identify c-MAF-regulated superenhancer genes, we overlapped our previously published H3K27ac ChIP-seq dataset on t(14;16) MM cell lines with c-MAF RNA-seq data. We found signal enrichment of H3K27ac at ZC3H3 locus responsible for its transcriptional upregulation, and knockdown of ZC3H3 inhibited cell growth specifically in the t(14;16) subtype. Altogether, we demonstrated a non-canonical c-MAF role in epigenetics that is connected to its altered metabolic state, and suggest metabolic disruptions as a new therapeutic direction in t(14;16) myeloma. Citation Format: Phyllis SY Chong, Sze Lynn Julia Lim, Jianbiao Zhou, Aaron Chung Yong Leow, Wee Joo Chng. c-MAF-driven metabolic reprogramming mediates H3K27 hyperacetylation to regulate super enhancer-associated genes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3681.