The Mitochondrial Protein VDAC1 at the Crossroads of Cancer Cell Metabolism: The Epigenetic Link

Abstract

Carcinogenesis is a complicated process that involves the deregulation of epigenetics, resulting in cellular transformational events, such as proliferation, differentiation, and metastasis. Most chromatin-modifying enzymes utilize metabolites as co-factors or substrates and thus are directly dependent on such metabolites as acetyl-coenzyme A, S-adenosylmethionine, and NAD+. Here, we show that using specific siRNA to deplete a tumor of VDAC1 not only led to reprograming of the cancer cell metabolism but also altered several epigenetic-related enzymes and factors. VDAC1, in the outer mitochondrial membrane, controls metabolic cross-talk between the mitochondria and the rest of the cell, thus regulating the metabolic and energetic functions of mitochondria, and has been implicated in apoptotic-relevant events. We previously demonstrated that silencing VDAC1 expression in glioblastoma (GBM) U-87MG cell-derived tumors, resulted in reprogramed metabolism leading to inhibited tumor growth, angiogenesis, epithelial-mesenchymal transition and invasiveness, and elimination of cancer stem cells, while promoting the differentiation of residual tumor cells into neuronal-like cells. These VDAC1 depletion-mediated effects involved alterations in transcription factors regulating signaling pathways associated with cancer hallmarks. As the epigenome is sensitive to cellular metabolism, this study was designed to assess whether depleting VDAC1 affects the metabolism-epigenetics axis. Using DNA microarrays, q-PCR, and specific antibodies, we analyzed the effects of si-VDAC1 treatment of U-87MG-derived tumors on histone modifications and epigenetic-related enzyme expression levels, as well as the methylation and acetylation state, to uncover any alterations in epigenetic properties. Our results demonstrate that metabolic rewiring of GBM via VDAC1 depletion affects epigenetic modifications, and strongly support the presence of an interplay between metabolism and epigenetics.Cancers 2020, 12, 1031 2 of 25 cellular metabolic activity regulates transcriptional networks and cell-fate decisions via epigenetic programs involving metabolite-dependent effects on chromatin organization. Epigenetics refers to a change in chromatin that leads to the regulation of gene expression without alterations in the DNA sequence [6]. Epigenetic modifications include DNA methylation, and/or histone modifications by acetylation, ubiquitination, methylation, phosphorylation, sumoylation, glycosylation, and biotinylation, changes that play a critical role in many cellular processes [7][8][9][10][11][12][13]. The enzymes responsible for these modifications include histone acetyltransferases (HATs), histone deacetylases (HDACs), methyltransferases (KMTs), and demethylases (KDMs) [14][15][16].There is now an accumulation of evidence that the epigenome is sensitive to cellular metabolism and a link between metabolism and epigenetics [3][4][5][17][18][19] has been proposed, with epigenetics and gene transcription being influenced by products of metabolic pathways [...

Mitochondria and nucleus cross‐talk: Signaling in metabolism, apoptosis, and differentiation, and function in cancer

“…Therefore, mitochondria supplying these metabolites are involved in controlling chromatin modifications 4 . Since upon VDAC1 silencing, the mitochondrial metabolism is highly reduced, 16,17,67,68 it is expected that decreasing VDAC1 expression levels would alter epigenetic signaling, and thereby gene expression 23 …”

“…VDAC1 as the transporter providing substrates for chromatin modification is heavily implicated in epigenetic modifications and thereby in the regulation of nuclear function. Indeed, we recently demonstrated that metabolic rewiring seen after depleting VDAC1 in GBM tumors is a consequence of limiting the substrates for chromatin modification, thereby affecting the metabolism–epigenetic axis 23 …”

The Two-Way Relationship Between Calcium and Metabolism in Cancer

“…Finally, the possibility of targeting metabolic pathways and Ca 2+ dynamics to manipulate the epigenome is a fascinating idea. New findings are emerging (Arif et al, 2017;Lombardi et al, 2019;Amsalem et al, 2020), and it will now be critical to understand the mechanisms by which concerted alterations in metabolism and Ca 2+ signaling regulate epigenetic-mediated transcriptional control in cancer cells.…”

“…Recent studies have provided evidence for this link. Alteration of mitochondrial metabolism upon VDAC1 depletion in glioblastoma cells limits the production of essential metabolic mediators of epigenetic processes, such as NADH, citrate, and acetyl-CoA (Arif et al, 2017;Amsalem et al, 2020). The associated changes in histone acetylation and methylation have profound effects on tumor growth, suggesting that this intricate link between Ca 2+ , metabolism and epigenetics may be exploited as an innovative therapeutic strategy for glioblastoma and other cancers (Arif et al, 2017;Amsalem et al, 2020).…”

Advances in Therapeutic Targeting of Cancer Stem Cells within the Tumor Microenvironment: An Updated Review

“…The adipose tissue and adipose-derived cells are able to interact with CSCs and have been shown to promote fatty acid oxidation in CSCs and chemoresistance [ 201 ]. The mitochondria are also known to play a role in CSC chemoresistance [ 202 ]. This is unsurprising as the mitochondria are central to many cellular processes such as metabolism, signaling and apoptosis.…”