Lee Moon Hee, Sung Kyung, Beebe David, Huang Wei, Shapiro Dan, Miyamoto Shigeki, Abel E Jason
Department of Urology, University of Wisconsin-Madison, Madison, WI, 53705, USA.
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.
Oncogenesis. 2022 Oct 25;11(1):65. doi: 10.1038/s41389-022-00440-4.
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).
虽然SUMO蛋白酶SENP1在多种实体癌中发挥的重要作用已得到认可，但其在肾细胞癌（RCC）发病机制中的作用，尤其是在最主要的亚型——透明细胞肾细胞癌（ccRCC）中的作用，却鲜为人知。在此，我们发现ccRCC样本中高HIF2α与SENP1表达相结合预示着患者预后不良。利用表达高HIF2α但低SENP1的ccRCC细胞模型，我们发现SENP1的过表达减少了HIF2α的SUMO化和泛素化，增加了HIF2α的转录活性，并增强了与癌细胞侵袭、干性和上皮-间质转化相关基因的表达。相应地，高HIF2α和SENP1的ccRCC细胞在体外表现出侵袭增加和成球能力增强，在体内表现出局部侵袭和转移增加。最后，SENP1过表达使高HIF2α的ccRCC细胞对临床mTOR抑制剂依维莫司产生耐药性。这些结果表明，高SENP1和HIF2α表达相结合会使ccRCC患者预后特别差，并提示SENP1可能是治疗转移性肾细胞癌（mRCC）的一个有吸引力的新靶点。
