2. Academic Validation
  3. p52-ZER6/DAZAP1 axis promotes ferroptosis resistance and colorectal cancer progression via regulating SLC7A11 mRNA stabilization

p52-ZER6/DAZAP1 axis promotes ferroptosis resistance and colorectal cancer progression via regulating SLC7A11 mRNA stabilization

  • Acta Pharm Sin B. 2025 Apr;15(4):2039-2058. doi: 10.1016/j.apsb.2025.02.013.
Li Qiu 1 2,  Wenfang Li 1 2,  Lei Zhang 1 2,  Xia Zhang 1 2,  Hezhao Zhao 3,  Makoto Miyagishi 4,  Shourong Wu 1 2,  Vivi Kasim 1 2
Affiliations

Affiliations

  • 1 Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
  • 2 The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China.
  • 3 Department of Gastrointestinal Surgery, Chongqing University Cancer Hospital, Chongqing University, Chongqing 400030, China.
  • 4 Life Science Innovation, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki 305-0006, Japan.
PMID: 40486833 DOI: 10.1016/j.apsb.2025.02.013
Abstract

Resistance to Ferroptosis, a form of regulated cell death caused by disruptions in iron ion and intracellular redox homeostasis, is closely related to tumorigenesis and tumor drug resistance; therefore, targeting ferroptosis-related pathways has garnered attention as a potential antitumor therapeutic strategy. However, the molecular mechanisms underlying Ferroptosis resistance in tumor cells remain unknown. Zinc-finger Estrogen receptor interaction clone 6 (ZER6) consists of two isoforms with distinct N-termini, p52-ZER6 and p71-ZER6. ZER6 is upregulated in tumors and promotes tumorigenic potential; however, whether ZER6 is involved in tumor cell Ferroptosis resistance remains unknown. Herein, we identified p52-ZER6 as a novel regulator of tumor cell Ferroptosis resistance. p52-ZER6 promotes the transcriptional activity of DAZAP1, an RNA-binding protein. DAZAP1, in turn, enhances the stability of SLC7A11 mRNA by binding to its 3'-UTR region, thereby increasing SLC7A11 expression and cellular glutathione levels. This subsequently reduces lipid peroxide accumulation and enhances tumor cell Ferroptosis resistance, eventually promoting tumorigenic potential. These findings reveal a new function of p52-ZER6 in regulating SLC7A11 mRNA stability via DAZAP1, ultimately leading to Ferroptosis resistance and tumorigenic potential. Additionally, we also suggest targeting p52-ZER6 as a potential strategy to promote the efficacy of ferroptosis-based antitumor therapies.

Keywords

DAZAP1; RNA binding protein; SLC7A11; Tumor cell ferroptosis; ZER6; Zinc-finger protein; mRNA stabilization; p52-ZER6.

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