Abstract 521: The role of the E3 ubiquitin ligase Parkin in clear cell renal cell carcinoma

Abstract Introduction: The E3 ubiquitin ligase Parkin has been described in several cancer entities, including clear cell renal cell carcinoma (ccRCC). Decreased Parkin expression is associated with poor prognosis. We aimed to clarify the biological role of Parkin in ccRCC and to evaluate its expression in a clinically characterized renal cancer cohort. Methods: We analyzed cell lines and clinically annotated patient material with qPCR (n=63), immunohistochemistry (n=262), LC-mass spectrometry and performed functional analyses in cell line models. Results: We found that overexpression of Parkin results in a less aggressive phenotype in the clear cell renal cell carcinoma cell line 786-O indicated by lower migration and invasion. Mass spectrometry revealed decreased levels of several proteins in Parkin expressing cells. One of these proteins was cyclin kinase subunit 2 (CKS2). The introduction of a C431S mutation in the catalytic domain of the Parkin gene abolished the effect of decreased migration. In addition, knockdown of CKS2 in cells lacking Parkin caused decreased migration suggesting that the effect of Parkin is CKS2 mediated. Furthermore, the correlation of CKS2 and tumor grading is highly significant and high levels of CKS2 are associated with shorter survival times. Conclusions: Parkin plays a major role in ccRCC biology, regulation cell migration and invasion, possibly exerted by CKS2 signaling. In consequence CKS2 appears to be an interesting prognostic biomarker in clear cell renal cell carcinoma and might also serve as a new therapy target. Citation Format: Laura Kristin Esser, Vittorio Branchi, Farhad Shaker, Adrian Georg Simon, Carsten Stephan, Glen Kristiansen, Andreas Buness, Hubert Schorle, Marieta I. Toma. The role of the E3 ubiquitin ligase Parkin in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 521.