FOXM1/DEPDC1 feedback loop promotes hepatocarcinogenesis and represents promising targets for cancer therapy

福克斯M1 癌症研究 癌变 细胞生长 细胞周期 生物 基因敲除 癌症 细胞凋亡 遗传学
作者
Wei Wang,Chenquan Zeng,Q. Li,Zhiyuan Xiao,Leisheng Zhang,Qiangnu Zhang,Lili Ren
出处
期刊:Cancer Science [Wiley]
标识
DOI:10.1111/cas.16273
摘要

Abstract Forkhead box M1 (FOXM1) is a key regulator of mitosis and is identified as an oncogene involved in several kinds of human malignancies. However, how it induces carcinogenesis and related therapeutic approaches remains not fully understood. In this study, we aimed to identify a regulatory axis involving FOXM1 and its target gene DEP domain containing 1 (DEPDC1) and investigate their biological functions. FOXM1 bound to the promoter and transcriptionally induced DEPDC1 expression, in turn, DEPDC1 physically interacted with FOXM1, promoted its nuclear translocation, and reinforced its transcriptional activities. The FOXM1/DEPDC1 axis was indispensable for cancer cells, as evidenced by the fact that DEPDC1 rescued cell growth inhibition caused by FOXM1 knockdown, and silencing DEPDC1 efficiently attenuated tumor growth in a murine hepatocellular carcinoma model. Furthermore, strong positive associations between FOXM1/DEPDC1 axis and poor clinical outcome were observed in human hepatocellular carcinoma samples, further indicating their significance for hepatocarcinogenesis. Finally, we attempted to exploit immunotherapy approaches to target the FOXM1/DEPDC1 axis. Several HLA‐A24:02‐restricted T‐cell epitopes targeting FOXM1 or DEPDC1 were identified through bioinformatic analysis. Then, T cell receptor (TCR)‐engineered T cells targeting FOXM1 262‐270 or DEPDC1 294‐302 were successfully established and proved to efficiently eradicate tumor cells. Our findings highlight the significance of the FOXM1/DEPDC1 axis in the process of oncogenesis and indicate their potential as immunotherapy targets.

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