Abstract 3359: JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α-mediated glucose metabolism

Abstract

JMJD5, a JmjC-domain containing dioxygenase, is important for embryonic development and cancer growth. Here, we show that JMJD5 is up-regulated by hypoxia and is crucial for hypoxia-induced cell proliferation. JMJD5 interacts directly with PKM2, pyruvate kinase M2, to modulate metabolic flux in cancer cells. The JMJD5-PKM2 interaction resides at the intersubunit interface region of PKM2, which hinders PKM2 tetramerization and blocks pyruvate kinase activity. This interaction also influences translocation of PKM2 into the nucleus and promotes HIF-1α-mediated transactivation. JMJD5 knockdown inhibits the transcription of the PKM2-HIF-1α target genes involved in glucose metabolism, resulting in a reduction of glucose uptake and lactate secretion in cancer cells. JMJD5, along with PKM2 and HIF-1α are all recruited to the HRE (hypoxia response element) site in the LDHA and PKM2 loci, and mediates the recruitment of the latter two proteins. Our data uncovers a new mechanism whereby PKM2 can be regulated by factor-binding induced homo/hetero-oligomeric restructuring, paving the way to cell metabolic reprogram. Citation Format: Hung-Jung Wang, Ya-Ju Hsieh, Wen-Chi Cheng, Chun-Pu Lin, Yu-Shan Lin, So-Fang Yang, Chung-Ching Chen, Yoshihiro Izumiya, Jau-Song Yu, Hsing-Jien Kung, Wen-Ching Wang. JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α-mediated glucose metabolism. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3359. doi:10.1158/1538-7445.AM2014-3359

JMJD8 Regulates Angiogenic Sprouting and Cellular Metabolism by Interacting With Pyruvate Kinase M2 in Endothelial Cells

“…35 Interestingly, JMJD5, a closely related family member which was previously shown to negatively regulate osteoclastogenesis and human circadian systems, was recently identified to regulate the nuclear translocation of PKM2 and thereby reprogramming HIF-1α-mediated glucose metabolism. 31,36,37 This regulation is consistent with our observation that JMJD8 is enhancing the metabolic activity of ECs by increasing the oxygen consumption and the maximal glycolytic function. Of note, we also showed a modulation of maximal oxygen consumption by JMJD8, indicating that mitochondrial function may be affected beyond the level of pyruvate formation.…”

“…31,32 Analyzing proteins bound to JMJD8 revealed enzymes that have been shown to be important regulators of metabolism like PKM2 and phosphofructokinase. Metabolism controls angiogenesis.…”

l -cysteine reversibly inhibits glucose-induced biphasic insulin secretion and ATP production by inactivating PKM2

“…S7D). PKM2 subunit dissociation (tetramers to dimers/monomers) results in downregulating its activity (33)(34)(35). Thus, we investigated the effect of L-cysteine and DASA-10 treatment on the oligomerization states of PKM2 protein in MIN6 cells using native SDS polyacrylamide gel electrophoresis (SDS/PAGE) based on the method of Nowakowski, et al (36).…”

Clipping of arginine-methylated histone tails by JMJD5 and JMJD7

“…In the hunt for histone arginine demethylase candidates, we hypothesized that one or more orphan JmjC domain-containing proteins, including JMJD4, JMJD5, JMJD7, and JMJD8, may be such a candidate. JMJD5 has been reported to play a critical role in embryonic development (19,20). The exact functions of JMJD5 remain controversial.…”