Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Institute of Health Service and Transfusion Medicine, Beijing, 100850, China.
Cell Death Dis. 2024 Jan 5;15(1):9. doi: 10.1038/s41419-023-06373-z.
Chromatin accessibility plays important roles in revealing the regulatory networks of gene expression, while its application in bladder cancer is yet to be fully elucidated. Chloride intracellular channel 3 (CLIC3) protein has been reported to be associated with the progression of some tumors, whereas the specific mechanism of CLIC3 in tumor remains unclear. Here, we screened for key genes in bladder cancer through the identification of transcription factor binding site clustered region (TFCR) on the basis of chromatin accessibility and TF motif. CLIC3 was identified by joint profiling of chromatin accessibility data with TCGA database. Clinically, CLIC3 expression was significantly elevated in bladder cancer and was negatively correlated with patient survival. CLIC3 promoted the proliferation of bladder cancer cells by reducing p21 expression in vitro and in vivo. Mechanistically, CLIC3 interacted with NAT10 and inhibited the function of NAT10, resulting in the downregulation of ac4C modification and stability of p21 mRNA. Overall, these findings uncover an novel mechanism of mRNA ac4C modification and CLIC3 may act as a potential therapeutic target for bladder cancer.
染色质可及性在揭示基因表达的调控网络方面起着重要作用，但其在膀胱癌中的应用尚未完全阐明。氯离子细胞内通道 3（CLIC3）蛋白已被报道与一些肿瘤的进展有关，而 CLIC3 在肿瘤中的具体机制尚不清楚。在这里，我们通过鉴定染色质可及性和 TF 基序上的转录因子结合位点聚集区（TFCR），筛选了膀胱癌中的关键基因。CLIC3 通过与 TCGA 数据库的联合分析染色质可及性数据来鉴定。临床上，CLIC3 在膀胱癌中表达显著上调，与患者的生存呈负相关。CLIC3 通过体外和体内降低 p21 表达促进膀胱癌细胞的增殖。在机制上，CLIC3 与 NAT10 相互作用并抑制 NAT10 的功能，导致 ac4C 修饰和 p21 mRNA 稳定性下调。总的来说，这些发现揭示了 mRNA ac4C 修饰的新机制，CLIC3 可能成为膀胱癌的潜在治疗靶点。
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