p52-ZER6/DAZAP1 axis promotes ferroptosis resistance and colorectal cancer progression via regulating SLC7A11 mRNA stabilization.
10.1016/j.apsb.2025.02.013
- Author:
Li QIU
1
;
Wenfang LI
1
;
Lei ZHANG
1
;
Xia ZHANG
1
;
Hezhao ZHAO
2
;
Makoto MIYAGISHI
3
;
Shourong WU
1
;
Vivi KASIM
1
Author Information
1. Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
2. Department of Gastrointestinal Surgery, Chongqing University Cancer Hospital, Chongqing University, Chongqing 400030, China.
3. Life Science Innovation, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki 305-0006, Japan.
- Publication Type:Journal Article
- Keywords:
DAZAP1;
RNA binding protein;
SLC7A11;
Tumor cell ferroptosis;
ZER6;
Zinc-finger protein;
mRNA stabilization;
p52-ZER6
- From:
Acta Pharmaceutica Sinica B
2025;15(4):2039-2058
- CountryChina
- Language:English
-
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.
