title: CHIP/Stub1 regulates the Warburg effect by promoting degradation of PKM2 in ovarian carcinoma.
abstract: Tumor cells preferentially adopt aerobic glycolysis for their energy supply, a phenomenon known as the Warburg effect. It remains a matter of debate as to how the Warburg effect is regulated during tumor progression. Here, we show that CHIP (carboxyl terminus of Hsc70-interacting protein), a U-box E3 ligase, suppresses tumor progression in ovarian carcinomas by inhibiting aerobic glycolysis. While CHIP is downregulated in ovarian carcinoma, induced expression of CHIP results in significant inhibition of the tumor growth examined by in vitro and in vivo experiments. Reciprocally, depletion of CHIP leads to promotion of tumor growth. By a SiLAD proteomics analysis, we identified pyruvate kinase isoenzyme M2 (PKM2), a critical regulator of glycolysis in tumors, as a target that CHIP mediated for degradation. Accordingly, we show that CHIP regulates PKM2 protein stability and thereafter the energy metabolic processes. Depletion or knockout of CHIP increased the glycolytic products in both tumor and mouse embryonic fibroblast cells. Simultaneously, we observed that CHIP expression inversely correlated with PKM2 levels in human ovarian carcinomas. This study reveals a mechanism that the Warburg effect is regulated by CHIP through its function as an E3 ligase, which mediates the degradation of PKM2 during tumor progression. Our findings shed new light into understanding of ovarian carcinomas and may provide a new therapeutic strategy for ovarian cancer.
authors.affiliation: The Key Laboratory for Cell Proliferation and Regulation Biology of Ministry of Education, Department of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China.|State Key Laboratory of Membrane Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Shang
authors.affiliation: The Key Laboratory for Cell Proliferation and Regulation Biology of Ministry of Education, Department of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: He
authors.affiliation: State Key Laboratory of Membrane Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Gynecology and Obstetrics, The Third Affiliated Hospital, Zhengzhou University, Zhengzhou, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Membrane Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Membrane Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Membrane Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Membrane Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.affiliation: State Key Laboratory of Membrane Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Key Laboratory for Cell Proliferation and Regulation Biology of Ministry of Education, Department of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China.
authors.forename: G
authors.initials: G
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Membrane Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.
authors.forename: F
authors.initials: F
authors.lastname: Ren
authors.affiliation: Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.affiliation: School of Pathology and Laboratory Medicine, The University of Western Australia (M504), Crawley, WA, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.affiliation: School of Surgery, The University of Western Australia (M509), Crawley, WA, Australia.|St John of God HealthCare, The Bendat Family Comprehensive Cancer Centre, Subiaco, WA, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Zeps
authors.affiliation: The Key Laboratory for Cell Proliferation and Regulation Biology of Ministry of Education, Department of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: The Key Laboratory for Cell Proliferation and Regulation Biology of Ministry of Education, Department of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China.
authors.forename: D
authors.initials: D
authors.lastname: He
authors.affiliation: State Key Laboratory of Membrane Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Chang
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D006019:Glycolysis; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D011770:Pyruvate Kinase; D013963:Thyroid Hormones; D044767:Ubiquitin-Protein Ligases; D000097810:Thyroid Hormone-Binding Proteins; C467728:STUB1 protein, human