转录的失调是癌症的标志，包括膀胱癌（BLCA）。使用携带单导RNA（sgRNA）靶向人类转录因子和染色质修饰因子的CRISPR-Cas9筛选方法用于揭示对BLCA细胞增殖和存活至关重要的基因。结果表明，核转录因子Y亚单位γ（NFYC）-37能促进BLCA细胞增殖和肿瘤生长，而NFYC-50则不能。机制上，NFYC-37与CBP和SREBP2相互作用以激活mevalonate通路转录，促进胆固醇生物合成。然而，NFYC-50比NFYC-37更多地招募了精氨酸甲基转移酶CARM1来甲基化CBP，从而阻断了CBP-SREBP2的相互作用，进而抑制了mevalonate通路。重要的是，靶向mevalonate通路的他汀类药物能够抑制NFYC-37诱导的细胞增殖和肿瘤生长，这表明需要进行一项以他汀类药物治疗NFYC-37水平高的BLCA患者的临床试验，因为大多数BLCA患者NFYC-37水平较高。版权所有，禁止转载。

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.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.