TFE3-rearranged renal cell carcinoma (TFE3-RCC) is an aggressive kidney cancer driven by oncogenic TFE3 fusion transcription factors, yet the molecular machinery that enables these fusions to reprogram transcription and drive tumor growth remains poorly defined. Here, we identify the Cyclin C-CDK8/19 Mediator kinase module as an essential co-regulator of TFE3 fusion driven transcriptional programs and tumorigenesis. Inducible expression of PRCC-TFE3 in HK-2 cells, immortalized from normal renal epithelial cells, triggered a robust oncogene-induced senescence (OIS) phenotype. Using OIS as a functional readout, we performed a genome-wide CRISPR/Cas9 loss-of-function screen and identified CCNC, encoding Cyclin C, as an essential gene required for PRCC-TFE3 activity. Genetic disruption of CCNC or pharmacologic inhibition of CDK8/19 abrogated PRCC-TFE3 induced OIS, establishing the Mediator kinase module as a critical cofactor for PRCC-TFE3 dependent transcription. Mechanistically, PRCC-TFE3 promoted nuclear accumulation of Cyclin C and their co-occupancy at genomic regions bound and transcriptionally activated by PRCC-TFE3. RNA sequencing revealed that PRCC-TFE3 induced transcriptional programs, including lysosomal, TFEB-associated, and metabolic pathways, were broadly suppressed by CDK8/19 inhibition. Importantly, while PRCC-TFE3 and Cyclin C-CDK8/19 drive OIS in non-cancerous renal epithelial cells, this same transcriptional axis exerts a context dependent pro-tumorigenic function in TFE3-RCC. In xenografts established from patient derived TFE3-RCC cell lines, genetic deletion of CCNC suppressed tumor growth, whereas in an orthotopic syngeneic TFE3-RCC mouse model, pharmacologic CDK8/19 inhibition significantly reduced tumor progression. These findings define the Mediator kinase module as a mechanistic and therapeutic vulnerability in PRCC-TFE3 driven TFE3-RCC, providing a rationale for mechanism based targeted therapy.
Neoplasia (New York, N.Y.). 2026 Mar 16 [Epub ahead of print]
Shoichiro Kuroda, Shintaro Funasaki, Hidekazu Nishizawa, Laura S Schmidt, Ryoma Kurahashi, Takaaki Ito, Yuichiro Arima, Miwa Tanaka, Atsuya Kitada, Amy M James, Hisashi Hasumi, Ryosuke Jikuya, Kazuhide Makiyama, Daisuke Kurotaki, Takashi Minami, Simone Difilippantonio, W Marston Linehan, Yuichi Oike, Tomohiro Sawa, Yasuhito Tanaka, Toshio Suda, Ryuji Yokokawa, Takuro Nakamura, Masaya Baba, Tomomi Kamba
Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan., Divison of Molecular and Vascular Biology, IRDA, Kumamoto University, Kumamoto 860-0811, Japan., Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA., Department of Medical Technology, Faculty of Health Sciences, Kumamoto Health Science University, Kumamoto 861-5598, Japan., Department of Anatomy and Neurobiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan., Project for Cancer Epigenomics, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan., Department of Micro Engineering, Graduate School of Engineering, Kyoto University, Kyoto 615-8540, Japan., Animal research Technical Support, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Department of Urology, Yokohama City University Graduate School of Medicine, Kanagawa 236-0004, Japan., Laboratory of Chromatin Organization in Immune Cell Development, International Research Center for Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan., Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan., Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan., Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan., State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin, China., Department of Experimental Pathology, Institute of Medical Science, Tokyo Medical University, Tokyo 160-8402, Japan., Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan. Electronic address: .