Histone Acyl Code in Precision Oncology: Mechanistic Insights from Dietary and Metabolic Factors

Abstract

Cancer etiology involves complex interactions between genetic and non-genetic factors, with epigenetic mechanisms serving as key regulators at multiple stages of pathogenesis. Poor dietary habits contribute to cancer predisposition by impacting DNA methylation patterns, non-coding RNA expression, and histone epigenetic landscapes. Histone post-translational modifications (PTMs), including acyl marks, act as a molecular code and play a crucial role in translating changes in cellular metabolism into enduring patterns of gene expression. As cancer cells undergo metabolic reprogramming to support rapid growth and proliferation, nuanced roles have emerged for dietary- and metabolism-derived histone acylation changes in cancer progression. Specific types and mechanisms of histone acylation, beyond the standard acetylation marks, shed light on how dietary metabolites reshape the gut microbiome, influencing the dynamics of histone acyl repertoires. Given the reversible nature of histone PTMs, the corresponding acyl readers, writers, and erasers are discussed in this review in the context of cancer prevention and treatment. The evolving 'acyl code' provides for improved biomarker assessment and clinical validation in cancer diagnosis and prognosis.

Keywords: acyl code; cancer; diet; epigenetics; histones; metabolism.

Figure 1

Dietary metabolites regulate cancer risk by modulating the histone acylation landscape. Dietary and metabolic alterations represent non-genetic/environmental risk factors influencing histone acylation during cancer development and progression. The right side of the diagram illustrates risk factors that increase cancer development through epigenetic mechanisms, such as an increase in histone methylation and a low acetylation/acylation ratio. On the left side, the diagram demonstrates how a healthy lifestyle and dietary metabolites that increase the diversity of the gut microbiota alter histone acetylation/acylation patterns. Increased levels of histone acyl-CoA precursors from both dietary and cellular metabolism contribute to chromatin decondensation through HDAC inhibition and the removal of repressive histone marks, thereby reducing the risk of cancer. Key abbreviations: MAT: methionine adenosyltransferase, HMT: histone methyltransferase, TET: ten-eleven translocation, ACC: acetyl-CoA carboxylase, ACSS2: acetyl-CoA synthetase 2, BD: bromodomain reader, PHD: plant homeodomain reader, HDACs: histone deacetylases, SAM: S-adenosyl methionine, PRC2: polycomb repressive complex 2, αKG: alpha ketoglutarate, PAHs: polycyclic aromatic hydrocarbons, HAAs: heterocyclic aromatic amines, NOCs: N-nitroso compounds, PhIP: 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, me3: H3K27me3, me1: H3K4me1, AhR: aryl hydrocarbon receptor, CRT: crotonase, me: methyl. Created with BioRender.com, accessed on 26 January 2024.