The SUMO protease SENP1 promotes aggressive behaviors of high HIF2α expressing renal cell carcinoma cells

Moon Hee Lee; Kyung Sung; David Beebe; Wei Huang; Dan Shapiro; Shigeki Miyamoto; E Jason Abel

doi:10.1038/s41389-022-00440-4

The SUMO protease SENP1 promotes aggressive behaviors of high HIF2α expressing renal cell carcinoma cells

Oncogenesis. 2022 Oct 25;11(1):65. doi: 10.1038/s41389-022-00440-4.

Authors

Moon Hee Lee¹, Kyung Sung^{2

3}, David Beebe^{3

4}, Wei Huang^{4

5}, Dan Shapiro^{1

4}, Shigeki Miyamoto^{6

7}, E Jason Abel^{8

9}

Affiliations

¹ Department of Urology, University of Wisconsin-Madison, Madison, WI, 53705, USA.
² Division of Cellular and Gene Therapies, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, the U.S. FDA, White Oak, MD, 20993, USA.
³ Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, 53705, USA.
⁴ University of Wisconsin Carbone Cancer Center, Madison, WI, 53705, USA.
⁵ Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA.
⁶ University of Wisconsin Carbone Cancer Center, Madison, WI, 53705, USA. smiyamot@wisc.edu.
⁷ Department of Oncology, University of Wisconsin-Madison, Madison, WI, 53705, USA. smiyamot@wisc.edu.
⁸ Department of Urology, University of Wisconsin-Madison, Madison, WI, 53705, USA. abel@urology.wisc.edu.
⁹ University of Wisconsin Carbone Cancer Center, Madison, WI, 53705, USA. abel@urology.wisc.edu.

Abstract

While an important role for the SUMO protease SENP1 is recognized in multiple solid cancers, its role in renal cell carcinoma (RCC) pathogenesis, particularly the most dominant subtype, clear cell RCC (ccRCC), is poorly understood. Here we show that a combination of high HIF2α and SENP1 expression in ccRCC samples predicts poor patient survival. Using ccRCC cell models that express high HIF2α but low SENP1, we show that overexpression of SENP1 reduces sumoylation and ubiquitination of HIF2α, increases HIF2α transcriptional activity, and enhances expression of genes associated with cancer cell invasion, stemness and epithelial-mesenchymal transition. Accordingly, ccRCC cells with high HIF2α and SENP1 showed increased invasion and sphere formation in vitro, and local invasion and metastasis in vivo. Finally, SENP1 overexpression caused high HIF2α ccRCC cells to acquire resistance to a clinical mTOR inhibitor, everolimus. These results reveal a combination of high SENP1 and HIF2α expression gives particularly poor prognosis for ccRCC patients and suggest that SENP1 may be an attractive new target for treating metastatic RCC (mRCC).

Abstract

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