Fang Ping, Yu Yang, Ma Yukun, Yan Yong, Wu Gang, Liu Sizhong, Wang Changbing, Li Weijian, Yu Tonghui, Fang Xiangdong, Wang Zishu
Department of Oncology, The902nd Hospital of the PLA Joint Logistics Support Force, Bengbu, China.
Department of Clinical Medicine, Naval Medical University, Shanghai, China.
Epigenomics. 2025 Jul 16:1-15. doi: 10.1080/17501911.2025.2530923.
Bladder cancer remains a prevalent malignancy with limited targeted therapies. Circular RNAs have emerged as critical regulators in cancer biology, though their role in ferroptosis remains largely unexplored.
The expression of circPPP6R1 was examined in BC tissues and cell lines. Functional assays, including Transwell migration, invasion, colony formation, and multiple ferroptosis-related assays, were conducted in vitro and in vivo. Mechanistic studies involved RNA pull-down, RIP, FISH, and mass spectrometry to identify circPPP6R1-interacting proteins.
circPPP6R1 was significantly downregulated in BC and its overexpression inhibited BC cell proliferation, migration, and invasion. Notably, circPPP6R1 enhanced ferroptosis in BC cells. Mechanistically, circPPP6R1 directly bound to UHRF1 and facilitated its ubiquitin-mediated degradation. UHRF1 was found to be highly expressed in BC tissues and correlated with adverse clinicopathological features. Rescue experiments confirmed that the tumor-suppressive effect of circPPP6R1 was mediated through UHRF1-dependent ferroptosis induction.
Our study identifies circPPP6R1 as a novel ferroptosis-promoting circRNA that suppresses BC progression by targeting UHRF1. These findings highlight the circPPP6R1/UHRF1 axis as a potential therapeutic target in bladder cancer.
膀胱癌仍然是一种常见的恶性肿瘤，靶向治疗有限。环状RNA已成为癌症生物学中的关键调节因子，但其在铁死亡中的作用仍 largely unexplored。
检测了circPPP6R1在膀胱癌组织和细胞系中的表达。在体外和体内进行了功能实验，包括Transwell迁移、侵袭、集落形成以及多种与铁死亡相关的实验。机制研究涉及RNA下拉、RIP、FISH和质谱分析，以鉴定与circPPP6R1相互作用的蛋白质。
circPPP6R1在膀胱癌中显著下调，其过表达抑制了膀胱癌细胞的增殖、迁移和侵袭。值得注意的是，circPPP6R1增强了膀胱癌细胞的铁死亡。机制上，circPPP6R1直接与UHRF1结合并促进其泛素介导的降解。发现UHRF1在膀胱癌组织中高表达，并与不良临床病理特征相关。挽救实验证实，circPPP6R1的抑癌作用是通过UHRF1依赖的铁死亡诱导介导的。
我们的研究确定circPPP6R1是一种新型的促进铁死亡的环状RNA，它通过靶向UHRF1抑制膀胱癌进展。这些发现突出了circPPP6R1/UHRF1轴作为膀胱癌潜在治疗靶点的作用。
