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: Y Shang, J He, Y Wang, Q Feng, Y Zhang, J Guo, J Li, S Li, Y Wang, G Yan, F Ren, Y Shi, J Xu, N Zeps, Y Zhai, D He, Z Chang
• Journal: Oncogene (Oncogene) Vol. 36 Issue 29 Pg. 4191-4200 (07 20 2017) ISSN: 1476-5594 [Electronic] England
• PMID: 28346425 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Membrane Proteins
• Thyroid Hormones
• STUB1 protein, human
• Ubiquitin-Protein Ligases
• Pyruvate Kinase

Topics

• Animals
• Carrier Proteins (genetics, metabolism)
• Cell Line, Tumor
• Down-Regulation
• Female
• Glycolysis
• HEK293 Cells
• Heterografts
• Humans
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Ovarian Neoplasms (enzymology, genetics, metabolism, pathology)
• Pyruvate Kinase (genetics, metabolism)
• Signal Transduction
• Thyroid Hormones (genetics, metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Thyroid Hormone-Binding Proteins