1. Lipid metabolism: new twists to the Yin and Yang of PKM2 in cancer
- Author
-
Ze'ev Ronai and Ali Khateb
- Subjects
Thyroid Hormones ,Pyruvate Kinase ,Breast Neoplasms ,Biology ,PKM2 ,General Biochemistry, Genetics and Molecular Biology ,Cell Line, Tumor ,medicine ,Animals ,Homeostasis ,Humans ,News & Views ,Fatty acid homeostasis ,Molecular Biology ,Mice, Knockout ,General Immunology and Microbiology ,General Neuroscience ,Intracellular Signaling Peptides and Proteins ,Membrane Proteins ,Cancer ,Lipid metabolism ,Articles ,medicine.disease ,Lipid Metabolism ,Xenograft Model Antitumor Assays ,Transmembrane protein ,Cancer treatment ,Gene Expression Regulation, Neoplastic ,Leukemia, Myeloid, Acute ,Cholesterol ,Cancer cell ,Cancer research ,Female ,Carrier Proteins ,Sterol Regulatory Element Binding Protein 1 ,Pyruvate kinase - Abstract
The pyruvate kinase M2 isoform (PKM2) is preferentially expressed in cancer cells to regulate anabolic metabolism. Although PKM2 was recently reported to regulate lipid homeostasis, the molecular mechanism remains unclear. Herein, we discovered an ER transmembrane protein 33 (TMEM33) as a downstream effector of PKM2 that regulates activation of SREBPs and lipid metabolism. Loss of PKM2 leads to up-regulation of TMEM33, which recruits RNF5, an E3 ligase, to promote SREBP-cleavage activating protein (SCAP) degradation. TMEM33 is transcriptionally regulated by nuclear factor erythroid 2-like 1 (NRF1), whose cleavage and activation are controlled by PKM2 levels. Total plasma cholesterol levels are elevated by either treatment with PKM2 tetramer-promoting agent TEPP-46 or by global PKM2 knockout in mice, highlighting the essential function of PKM2 in lipid metabolism. Although depletion of PKM2 decreases cancer cell growth, global PKM2 knockout accelerates allografted tumor growth. Together, our findings reveal the cell-autonomous and systemic effects of PKM2 in lipid homeostasis and carcinogenesis, as well as TMEM33 as a bona fide regulator of lipid metabolism.
- Published
- 2021