UFMylation: A supervisor of the HIF1α pathway and a potential therapeutic target for anti- PD-1 combination therapy in hypoxic tumors

• 成果类型: Article
• 署名作者: Zou, Yongkang; Wang, Zhaoxiang; Jiang, Qiang; Kong, Xia; Ma, Xiaohe; Liang, Zhengyan; Wang, Zhiguo; Chen, Beiying; Yuan, Jiao; Wen, Jiayue; Ye, Sheng; Yan, Yubin; Li, Binbin; Xiong, Xing-dong; Liu, Xin-guang; He, Zhiwei; Cai, Yafei; Zhou, Junzhi
• 署名单位: Shenzhen Bay Laboratory; Guangdong Medical University; Nanjing Agricultural University; Shandong Academy of Agricultural Sciences; Hangzhou Normal University; Guangzhou Medical University; Guangzhou Laboratory; Chinese Academy of Sciences; Guangzhou Institute of Biomedicine & Health, CAS
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11003
• DOI: 10.1073/pnas.2500562122
• 发表日期: 2025-07-08
• 关键词: ufm1 e3 ligase; cancer; reveals; protein; uba5; p53

摘要

Activation of hypoxia signaling has been identified as an innate resistance signature against anti- PD- 1 therapy, suggesting its potential as a target for combination treatments. Here, we demonstrate that UFMylation modification of HIF1 alpha stabilizes the protein by antagonizing its ubiquitination and proteasomal degradation under hypoxic conditions. Mechanistically, depletion of UFL1 or defective UFMylation increases HIF1 alpha binding to p53, promoting its degradation. Depletion of UFL1 or UBA5, or defective UFMylation of HIF1 alpha, destabilizes HIF1 alpha, significantly inhibiting tumor growth and development in vitro and in xenograft mouse models. Defective UFMylation of HIF1 alpha enhances the response to anti- PD- 1 therapy in xenograft models. Clinically, UBA5 expression is upregulated in breast cancer tissues, and a selective UBA5 inhibitor reduces UFMylation activity and HIF1 alpha protein levels, thereby enhancing anti- PD- 1 combination therapy in mouse tumor models. Our findings highlight UFMylation as a critical posttranslational modification for the HIF1 alpha pathway and a promising therapeutic target in hypoxic tumors.