Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells

Abstract

The retinoblastoma tumor suppressor protein pRb restricts cell growth through inhibition of cell cycle progression. Increasing evidence suggests that pRb also promotes differentiation, but the mechanisms are poorly understood, and the key question remains as to how differentiation in tumor cells can be enhanced in order to diminish their aggressive potential. Previously, we identified the histone demethylase KDM5A (lysine [K]-specific demethylase 5A), which demethylates histone H3 on Lys4 (H3K4), as a pRB-interacting protein counteracting pRB's role in promoting differentiation. Here we show that loss of Kdm5a restores differentiation through increasing mitochondrial respiration. This metabolic effect is both necessary and sufficient to induce the expression of a network of cell typespecific signaling and structural genes. Importantly, the regulatory functions of pRB in the cell cycle and differentiation are distinct because although restoring differentiation requires intact mitochondrial function, it does not necessitate cell cycle exit. Cells lacking Rb1 exhibit defective mitochondria and decreased oxygen consumption. Kdm5a is a direct repressor of metabolic regulatory genes, thus explaining the compensatory role of Kdm5a deletion in restoring mitochondrial function and differentiation. Significantly, activation of mitochondrial function by the mitochondrial biogenesis regulator Pgc-1α (peroxisome proliferator-activated receptor γ-coactivator 1α; also called PPARGC1A) a coactivator of the Kdm5a target genes, is sufficient to override the differentiation block. Overexpression of Pgc-1α, like KDM5A deletion, inhibits cell growth in RB-negative human cancer cell lines. The rescue of differentiation by loss of KDM5A or by activation of mitochondrial biogenesis reveals the switch to oxidative phosphorylation as an essential step in restoring differentiation and a less aggressive cancer phenotype.

Mitochondrial control through nutritionally regulated global histone H3 lysine-4 demethylation

“…Similarly to our work, mitochondrial respiration has been identified as a target of JARID1A repression in mouse embryonic fibroblasts, where JARID1A knockdown restores the ability of cells lacking Retinoblastoma tumor suppressor protein function to differentiate in a manner that is dependent on its demethylase activity37. In a finding that is superficially at odds with our results and those from human cells, in Drosophila melanogaster , Lid, the sole JARID ortholog present in this organism, functions to activate mitochondrial genes in a manner that is independent of its enzymatic activity38.…”

Metabolic Reprogramming of Pancreatic Cancer Mediated by CDK4/6 Inhibition Elicits Unique Vulnerabilities

“…Interestingly, in fibroblastic models RB loss is associated with increased glutamine utilization (Clem and Chesney, 2012; Reynolds et al, 2014), and loss of RBF has been associated with altered glutamine catabolism in drosophila (Nicolay et al, 2013). Recent studies have shown that loss of RB can lead to decreased oxidative phosphorylation and more dependency on glycolytic metabolism (Nicolay et al, 2015; Varaljai et al, 2015). Consonantly, E2F1 and RB in tissue can provide a critical node of regulation between proliferation and metabolic activity (Blanchet et al, 2011; Lopez-Mejia and Fajas, 2015).…”

JARID1 Histone Demethylases: Emerging Targets in Cancer

“…A similar role for JARID1C is suggested by the brain-specific expression in Zebrafish embryos and neural defects following its knockdown [86]. JARID1 proteins are also implicated in later development and adult tissue homeostasis, including myogenic differentiation of embryonic fibroblasts [111]. A role for JARID1B in postnatal mammary gland development was observed in a viable strain of JARID1B knockout mice [33] and mice where only JARID1B’s ARID domain was deleted [106].…”