Metformin targets histone acetylation in cancer-prone epithelial cells

Abstract

The usage of metabolic intermediates as substrates for chromatin-modifying enzymes provides a direct link between the metabolic state of the cell and epigenetics. Because this metabolism-epigenetics axis can regulate not only normal but also diseased states, it is reasonable to suggest that manipulating the epigenome via metabolic interventions may improve the clinical manifestation of age-related diseases including cancer. Using a model of BRCA1 haploinsufficiency-driven accelerated geroncogenesis, we recently tested the hypothesis that: 1.) metabolic rewiring of the mitochondrial biosynthetic nodes that overproduce epigenetic metabolites such as acetyl-CoA should promote cancer-related acetylation of histone H3 marks; 2.) metformin-induced restriction of mitochondrial biosynthetic capacity should manifest in the epigenetic regulation of histone acetylation. We now provide one of the first examples of how metformin-driven metabolic shifts such as reduction of the 2-carbon epigenetic substrate acetyl-CoA is sufficient to correct specific histone H3 acetylation marks in cancer-prone human epithelial cells. The ability of metformin to regulate mitonuclear communication and modulate the epigenetic landscape in genomically unstable pre-cancerous cells might guide the development of new metabolo-epigenetic strategies for cancer prevention and therapy. KEYWORDS BRCA1; epigenetics; histone acetylation; metformin; mitochondria While metabolic rewiring of cancer cells can be a direct consequence of the concerted action of oncogenes and tumor suppressor genes that drive aberrant growth of cancer tissues, altered metabolism might also play a primary, causative role in oncogenesis. Accordingly, metabolic reprogramming is increasingly appreciated as a candidate hallmark of tumorigenesis. [1][2][3][4][5] In a recently proposed metabolism-centered model of carcinogenesis, known as geroncogenesis 2 the possibility of acquiring genetic aberrations increases when aging itself operates as a driver of cancer-like metabolic landscapes. Tumor formation might therefore depend not only on accumulating mutations in the genome, but also on the decline in the homeostasis or metabolic health that naturally occurs in aging cells. Indeed, after many years of being subordinated to the nucleus as the commander-in-chief, able to initiate biological events, the capacity of metabolism to independently dictate cellular actions is increasingly recognized among most cell biologists. Accordingly, the research community now acknowledges that aging-driven alteration of metabolic homeostasis might be sufficient to favor an imbalance in self-amplifying metabolic landscapes that ultimately manifest as aging-driven diseases, including cancer. 6Metabolic programs: From anabolic supporters of genomic instability to epigenetic regulators of carcinogenesisThe metabolic health of our cells might be a key determinant factor pushing the risk balance or cancer risk-meter toward health or the risk of cancer.1,2 On the one hand, genomic instability, a charac...

Precancer Atlas to Drive Precision Prevention Trials

“…Germline BRCA1 mutation reprograms breast epithelial cell metabolism towards mitochondrial-dependent biosynthesis and increased risk of oncogenesis. Metformin studies in BRCA1 haploinsufficiency-driven oncogenesis support potential prevention approaches in BRCA1 carriers: inhibition of complex I and restriction of mitochondrial-dependent biosynthetic intermediates (123) may open a new avenue for “starvation” strategies; and regulating mitochondrial-nuclear communication and modulating the epigenetic landscape (targeting histone acetylation) in genomically unstable precancerous cells (124), might guide the development of new metabolomic-epigenetic strategies. As with nuclear GWAS, certain mtDNA alterations modify (lower) risks of breast cancer in germline BRCA2 mutations (125).…”

AMPK: An Epigenetic Landscape Modulator

“…AMPK activated by metformin regulates histone acetylation in a metabolic state-dependent manner. For example, metformin reduces H3 acetylation by decreasing bioavailability of mitochondrial acetyl-CoA in breast cancer, bringing acetylation status to normal in promoters of cancer-specific genes [ 37 ].…”

Mitostemness

“…This mathematical approach predicted that regulating the stochastic translation of mitochondrial-driven metabolic inputs into resilient versus plastic cell states via epigenetics could promote the establishment of epigenomes refractory to (CSC-related) loss of cell fate and de-differentiation phenomena. In this context, apparently simple drugs such as the anti-diabetic biguanide metformin, which operates as a metabolo-epigenetic reprogrammer of the molecular conduits linking mitochondrial-driven synthesis of epigenetic metabolites with the structure and functioning of the epigenome [23][24][25][26], are now recognized as molecules that selectively target CSCs [27,28]. Metformin has been shown to potently and specifically suppress the undifferentiated stem cell compartment responsible for malignant carcinoma-like growth within tumor masses generated upon injection of induced pluripotent stem cells (iPSCs) into mice [29][30].…”