Department of Life Sciences conducted a seminar on 'Hypoxia-mediated epigenetic regulation of cancer cell metabolism

The Department of Life Sciences conducted a seminar titled 'Hypoxia-mediated epigenetic regulation of cancer cell metabolism' by Dr. Sanjeev Shukla, Associate Professor and Wellcome Trust/DBT India Alliance Fellow, Indian Institute of Science Education and Research (IISER), Bhopal on March 3, 2022, from 4 PM to 5 PM.

The hypoxic tumor microenvironment is one of the most critical factor that intricately modulates cellular metabolism. The co-regulatory mechanisms that exist between the key metabolic enzymes and the proliferative potential of the hypoxic breast cancer cells are largely unexplored. The M2 isoform of pyruvate kinase (PKM2) is well known to confer numerous adaptive advantages under hypoxia. Here, we have examined the non-canonical role of PKM2 as a transcriptional co-activator of key glycolytic enzymes that are hypoxia-inducible factor-1α (HIF-1α) targets. Differential gene expression profile has revealed 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) to be a novel gene regulated by the HIF-1α-PKM2-axis. Interestingly, in the absence of PKM2, the hypoxic regulation of PFKFB3 exhibits a decreased dependency on HIF-1α as the primary transcriptional regulator, establishing the vital role played by nuclear PKM2. We have uncovered that in the absence of HIF-1α and/or PKM2, HIF-2α occupies the hypoxia responsive elements (HREs) of PFKFB3 to maintain its expression at basal level. Under these conditions, the hypoxic breast cancer cells show decreased dependency on glycolysis coupled with an increase in the mitochondrial oxidative phosphorylation (OXPHOS). We have demonstrated that PKM2 inhibitor, Shikonin prevents the nuclear translocation of the glycolytic enzyme and suppresses the hypoxic induction of PFKFB3. Our findings highlight the benefits of targeting PKM2 to attenuate the proliferation of hypoxic breast cancer cells.