Histone Demethylase KDM5C Drives Prostate Cancer Progression by Promoting EMT

Abstract: Prostate cancer (PCa) poses a major public health problem in men. Metastatic PCa is incurable, and ultimately threatens the life of many patients. Mutations in tumor suppressor genes and oncogenes are important for PCa progression, whereas the role of epigenetic factors in prostate carcinogenesis is insufficiently examined. The histone demethylase KDM5C exerts important roles in tumorigenesis. KDM5C has been reported to be highly expressed in various cancer cell types, particularly in primary PCa. Here, we could show that KDM5C is highly upregulated in metastatic PCa. Functionally, in KDM5C knockdown cells migratory and invasion capacity was reduced. Interestingly, modulation of KDM5C expression influences several EMT signaling pathways (e.g., Akt/mTOR), expression of EMT transcription factors, epigenetic modifiers, and miR-205, resulting in increased expression of E-cadherin and reduced expression of N-cadherin. Mouse xenografts of KDM5C knockdown cells showed reduced tumor growth. In addition, the Akt/mTOR pathway is one of the classic signaling pathways to mediate tumor metabolic homeostasis, which is beneficial for tumor growth and metastasis. Taken together, our findings indicate that a combination of a selective KDM5C- and Akt/mTOR-inhibitor might be a new promising therapeutic strategy to reduce metastatic burden in PCa.Simple Summary: Prostate cancer is the most common cancer in men and is one of the leading causes of cancer-related deaths. During prostate cancer progression and metastasis, the epithelial cells can undergo epithelial–mesenchymal transition (EMT). Here, we show that the histone demethylase KDM5C is highly expressed in metastatic prostate cancer. We establish that stable clones silence KDM5C in prostate cancer cells. Knockdown of KDM5C leads to a reduced migratory and invasion capacity. This is associated with changes by multiple molecular mechanisms. This signaling subsequently modifies the expression of various transcription factors like Snail, Twist, and Zeb1/2, which are also known as master regulators of EMT. Taken together, our results indicate the potential to therapeutically target KDM5C either alone or in combination with Akt/mTOR-inhibitor in prostate cancer patients by targeting the EMT signaling pathways.