KDM8/JMJD5 as a dual coactivator of AR and PKM2 integrates AR/EZH2 network and tumor metabolism in CRPC

Abstract

During the evolution into castration or therapy resistance, prostate cancer cells reprogram the androgen responses to cope with the diminishing level of androgens, and undergo metabolic adaption to the nutritionally deprived and hypoxia conditions. AR (androgen receptor) and PKM2 (pyruvate kinase M2) have key roles in these processes. We report in this study, KDM8/JMJD5, a histone lysine demethylase/dioxygnase, exhibits a novel property as a dual coactivator of AR and PKM2 and as such, it is a potent inducer of castration and therapy resistance. Previously, we showed that KDM8 is involved in the regulation of cell cycle and tumor metabolism in breast cancer cells. Its role in prostate cancer has not been explored. Here, we show that KDM8's oncogenic properties in prostate cancer come from its direct interaction (1) with AR to affect androgen response and (2) with PKM2 to regulate tumor metabolism. The interaction with AR leads to the elevated expression of androgen response genes in androgen-deprived conditions. They include ANCCA/ATAD2 and EZH2, which are directly targeted by KDM8 and involved in sustaining the survival of the cells under hormone-deprived conditions. Notably, in enzalutamide-resistant cells, the expressions of both KDM8 and EZH2 are further elevated, so are neuroendocrine markers. Consequently, EZH2 inhibitors or KDM8 knockdown both resensitize the cells toward enzalutamide. In the cytosol, KDM8 associates with PKM2, the gatekeeper of pyruvate flux and translocates PKM2 into the nucleus, where the KDM8/PKM2 complex serves as a coactivator of HIF-1α to upregulate glycolytic genes. Using shRNA knockdown, we validate KDM8's functions as a regulator for both androgen-responsive and metabolic genes. KDM8 thus presents itself as an ideal therapeutic target for metabolic adaptation and castration-resistance of prostate cancer cells.

Protein kinase function of pyruvate kinase M2 and cancer

“…PKM2 deacetylation abolishes its nuclear protein kinase and transcription coactivator activities, leading to suppression of its nuclear oncogenic function and consequent tumor suppression and metastasis inhibition. KDM8, a histone lysine demethylase, binds directly to the interface area of PKM2 subunits, retarding PKM2 tetramer formation and promoting its nuclear translocation, where the KDM8/PKM2 complex acts as a coactivator of HIF-1α to induce the expression of glycolytic genes [ 64 , 65 ]. The data suggest that PKM2 may enter the nucleus as a monomer.…”

Therapeutic Targeting of MDR1 Expression by RORγ Antagonists Resensitizes Cross-Resistant CRPC to Taxane via Coordinated Induction of Cell Death Programs

“…Indeed, a number of E2F targets including TOP2A, BIRC5/survivin, and ANCCA/ATAD2 are strongly downregulated by the combination treatment. Interestingly, ANCCA/ATAD2 is a critical coactivator of E2Fs and AR, and is also a direct target of AR and E2Fs (44,47,48). We previously demonstrated that ANCCA/ATAD2 activates the expression of TOP2A and BIRC5 (44,49).…”

The epigenetic and transcriptional landscape of neuroendocrine prostate cancer

“…For example, pyruvate generated from glycolysis is the main substrate for acetyl-CoA, a central metabolite coordinating the activity of the histone acetyltransferase (HAT) enzymes. Treatment-induced NEPC tumours exhibit elevated expression of the histone lysine demethylase KDM8, which functions to reprogram metabolism toward aerobic glycolysis (Wang et al 2019). Moreover, MYCN, which is implicated in neuroendocrine lineage reprogramming, increases mitochondrial export of acetyl groups and upregulates the HAT GCN5 leading to elevated histone acetylation and DNA accessibility (Knoepfler et al 2006).…”