Epigenetic Control of Mitochondrial Fission Enables Self-Renewal of Stem-like Tumor Cells in Human Prostate Cancer

Abstract

Highlights d Distinct transcriptional programs characterize prostate CSC and bulk tumor cells d BRD4 promotes mitochondrial biogenesis and metabolic plasticity in prostate CSCs d Mitochondrial fission enables asymmetric division and prostate CSC self-renewal d BRD4 inhibitors block mitochondrial fission and hinder selfrenewal of prostate CSCs

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

“…Among the various bromodomain regulators, particularly interesting id BRD4, an epigenetic reader protein in the BET family, which binds to enhancers and super-enhnacers of several genes involved in the control of cell proliferation and involved in tumor cell transcriptional addiction. Several observations support BRD4 as a potential therapeutic target in prostate cancer: (a) SPOP mutations impair ubiquitin-dependent proteasomal degradation of BRD4, upregulating BRD4 levels; (b) DUB3 deubiquitinates BRD4, increasing its levels and promoting prostate cancer progression [727]; (c) BRD4 impedes mitochondrial fission at the level of prostate cancer stem cells through induction of mitochondrial fission factor (MFF) [728]; and (d) BRD4 regulates metastatic potential of castration-resistant prostate cancer through AHNAK, a large scaffolding protein linked to promotion of metastasis [729]; BRD4 and ZFX modulate noncanonical oncogenic functions of the AR splice varian 7 in CRPC cells [730].…”

Metabolic Plasticity and Epithelial-Mesenchymal Transition

“…As discussed above, the inhibition of metabolic enzymes such as ALDOA, GAPDH or FASN can prevent or revert EMT in cell models, as can the neutralization of acidic tumor environments. The recent observations that mesenchymal properties require fused mitochondria endowed with efficient TCA and OXHPOS [10], while prostate CSCs rely on mitochondrial fission [178], afford the prediction that interventions directly aimed at mitochondrial function or dynamics will produce differential effects on cell plasticity, and thus are worth exploring as antineoplastic strategies.…”

Mitochondrial fission promotes self-renewal and tumorigenic potential in prostate cancer

“…10 In prostate CSCs, we uncovered an important link between BRD4 function and regulation of mitochondria dynamics through the activation of Mitochondrial Fission Factor (MFF) transcription. 8 Blocking BRD4 by genetic knockdown or the BETi OTX015/MK-8628 impaired fission and segregation of mitochondria during asymmetric cell division (Figure 1(b)). This resulted in senescence selectively in CSCs and progressive loss of self-renewal capability.…”

“…This analysis revealed significantly divergent transcriptional programs in CSCs and BTCs. 8 Genes associated with proliferation, mitosis, and DNA replication were predominantly active in BTCs. Conversely, these pathways were underrepresented in CSCs, which exhibited preferential activation of metabolic and mitochondrial pathways.…”

“…The progressive exhaustion of prostate CSCs was due to the failed mitochondria segregation during asymmetric cell division and consequent selective impairment of their selfrenewal. 8 The efficacy of BETi towards prostate CSCs provides the opportunity to test the potential benefits of combining CSC-directed therapies with anticancer drugs affecting BTCs. This combinatorial strategy could reduce treatment failures by preventing the emergence of resistant CSCs and provide effective therapeutic options for patients with CRPC for which current treatment offers limited and not durable benefits.…”