NFYC-37 promotes tumor growth by activating the mevalonate pathway in bladder cancer.

Zefu Liu, Xianchong Zheng, Jiawei Chen, Lisi Zheng, Zikun Ma, Lei Chen, Minhua Deng, Huancheng Tang, Liwen Zhou, Tiebang Kang, Yuanzhong Wu, Zhuowei Liu

Journal: Cell reports 2023;42(8):112963

PMID: 37561631

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Abstract

Dysregulation of transcription is a hallmark of cancer, including bladder cancer (BLCA). CRISPR-Cas9 screening using a lentivirus library with single guide RNAs (sgRNAs) targeting human transcription factors and chromatin modifiers is used to reveal genes critical for the proliferation and survival of BLCA cells. As a result, the nuclear transcription factor Y subunit gamma (NFYC)-37, but not NFYC-50, is observed to promote cell proliferation and tumor growth in BLCA. Mechanistically, NFYC-37 interacts with CBP and SREBP2 to activate mevalonate pathway transcription, promoting cholesterol biosynthesis. However, NFYC-50 recruits more of the arginine methyltransferase CARM1 than NFYC-37 to methylate CBP, which prevents the CBP-SREBP2 interaction and subsequently inhibits the mevalonate pathway. Importantly, statins targeting the mevalonate pathway can suppress NFYC-37-induced cell proliferation and tumor growth, indicating the need for conducting a clinical trial with statins for treating patients with BLCA and high NFYC-37 levels, as most patients with BLCA have high NFYC-37 levels.

Address: Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China; Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China.; Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China.; Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China. Electronic address: [email protected].; Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China. Electronic address: [email protected].; Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China; Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China; Department of Urology, Sun Yat-sen University Cancer Center Gansu Hospital, Lanzhou 730000, Gansu, China. Electronic address: [email protected].

DOI: 10.1016/j.celrep.2023.112963