RNF20 Suppresses Tumorigenesis by Inhibiting the SREBP1c-PTTG1 Axis in Kidney Cancer

ABSTRACT

Elevated lipid metabolism promotes cancer cell proliferation. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancers, characterized by ectopic lipid accumulation. However, the relationship between aberrant lipid metabolism and tumorigenesis in ccRCC is not thoroughly understood. Here, we demonstrate that ring finger protein 20 (RNF20) acts as a tumor suppressor in ccRCC. RNF20 overexpression repressed lipogenesis and cell proliferation by inhibiting sterol regulatory element-binding protein 1c (SREBP1c), and SREBP1 suppression, either by knockdown or by the pharmacological inhibitor betulin, attenuated proliferation and cell cycle progression in ccRCC cells. Notably, SREBP1c regulates cell cycle progression by inducing the expression of pituitary tumor-transforming gene 1 (PTTG1), a novel target gene of SREBP1c. Furthermore, RNF20 overexpression reduced tumor growth and lipid storage in xenografts. In ccRCC patients, RNF20 downregulation and SREBP1 activation are markers of poor prognosis. Therefore, RNF20 suppresses tumorigenesis in ccRCC by inhibiting the SREBP1c-PTTG1 axis.

KEYWORDS:

• RNF20
• SREBP1c
• PTTG1
• ccRCC
• tumorigenesis

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SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at https://doi.org/10.1128/MCB.00265-17.

ACKNOWLEDGMENTS

We thank the members of the laboratory of adipocyte and metabolism research for helpful discussion. We also thank Jay Horton at the University of Texas Southwestern Medical Center for providing SREBP1c-deficient mice and Cho-Rok Jung of the Korea Research Institute of Bioscience and Biotechnology for sharing the pFlagCMV2-PTTG1 vector.

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the South Korea government (Ministry of Science, ICT and Future Planning; 2011-0018312 and NRF-2012M3A9B6055344) to J.B.K. This research was also supported by the NRF grant funded by the South Korea government (MSIP; 2015R1A2A2A01006813) to C.K. Y.G.J. was supported by the BK21 program.

We declare that we have no conflicts of interest.