Histone demethylase JMJD1A promotes urinary bladder cancer progression by enhancing glycolysis through coactivation of hypoxia inducible factor 1α

Abstract

High aerobic glycolysis not only provides energy to cancer cells, but also supports their anabolic growth. JMJD1A, a histone demethylase that specifically demethylates H3K9me1/2, is overexpressed in multiple cancers, including urinary bladder cancer (UBC). It is unclear whether JMJD1A could promote cancer cell growth through enhancing glycolysis. In this study, we found that downregulation of JMJD1A decreased UBC cell proliferation, colony formation and xenograft tumor growth. Knockdown of JMJD1A inhibited glycolysis by decreasing the expression of genes participated in glucose metabolism, including GLUT1, HK2, PGK1, PGM, LDHA and MCT4. Mechanistically, JMJD1A cooperated with hypoxia inducible factor 1α (HIF1α), an important transcription factor for glucose metabolism, to induce the glycolytic gene expression. JMJD1A was recruited to the promoter of glycolytic gene PGK1 to demethylate H3K9me2. However, the JMJD1A (H1120Y) mutant, which loses the demethylase activity, failed to cooperate with HIF1α to induce the glycolytic gene expression, and failed to demethylate H3K9me2 on PGK1 promoter, suggesting that the demethylase activity of JMJD1A is essential for its coactivation function for HIF1α. Inhibition of glycolysis through knocking down HIF1α or PGK1 decelerated JMJD1A-enhanced UBC cell growth. Consistent with these results, a positive correlation between JMJD1A and several key glycolytic genes in human UBC samples was established by analyzing a microarray-based gene expression profile. In conclusion, our study demonstrates that JMJD1A promotes UBC progression by enhancing glycolysis through coactivation of HIF1α, implicating that JMJD1A is a potential molecular target for UBC treatment.

Yes-associated protein (YAP) binds to HIF-1α and sustains HIF-1α protein stability to promote hepatocellular carcinoma cell glycolysis under hypoxic stress

“…HIF-1α directly up-regulates the expression of the glycolytic genes, e.g., PKM2 (pyruvate kinase M2) [7], HK2 (hexokinase 2), and LDHA (lactate dehydrogenase A) [8, 9], to promote glycolysis in tumors. On the other hand, some oncogenes cooperate with HIF-1α to increase HIF-1α stabilization and transcriptional activity, subsequently promoting hypoxic tumor cell glycolysis [10, 11]. Therefore, investigating the regulatory mechanism between HIF-1α and HCC cell glycolysis under hypoxic conditions is worthwhile.…”

Hypoxia Restrains Lipid Utilization via Protein Kinase A and Adipose Triglyceride Lipase Downregulation through Hypoxia-Inducible Factor

“…As an excellent genetic model organism, Caenorhabditis elegans has well-conserved mechanisms in response to various stress conditions, including hypoxia (20,(39)(40)(41). The C. elegans genome has hif-1, vhl-1, and egl-9, which encode proteins homologous to the mammalian HIF␣ subunit, VHL, and PHD, respectively.…”

A network of epigenomic and transcriptional cooperation encompassing an epigenomic master regulator in cancer

“…The cooperation network includes previously validated interactions of MYC, HIF1A, and AR in cancer but also highlights close association of KDM3A with transcriptional networks of factors rather studied in development and tissue differentiation like JUN, CEBPB, MYOD, SREBF1, SP1, MEIS1, ZEB1, or ELK1 (Table 1). By taking advantage of motif-specific target networks, KDM3A has the ability to induce glycolytic genes in urothelial bladder carcinoma 24,25 . Epigenomic regulation of SREBF1 activity has been reported to stimulate lipogenesis, and SREBP1 regulates lipid accumulation and cell cycle progression in androgen independent prostate cancer cell lines [26][27][28] 1), it is possible that the putative association with KDM3A steams from the fact that the closely cooperating AR frequently has FOX motifs nearby.…”