CPEB1 Controls NRF2 Proteostasis and Ferroptosis Susceptibility in Pancreatic Cancer

Zhang, Shuxia1,2; Huang, Jingnan3,4; Lan, Zhangzhang5; Xiao, Yanlin5; Liao, Youyou5; Basnet, Shiva5; Huang, Piying3; Li, Yunze1; Yan, Jingyu1; Sheng, Yuling1; Zhou, Wenwen1; Liu, Qi1; Tan, Haoyuan1; Tan, Yi1; Yuan, Leyong6; Wang, Lisheng2; Dai, Lingyun3,4; Zhang, Wenyong5; Du, Changzheng1,7,8,9

2024

10.7150/ijbs.95962

INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES   影响因子和分区

1449-2288

Pancreatic cancer is the deadliest malignancy with a poor response to chemotherapy but is potentially indicated for ferroptosis therapy. Here we identified that cytoplasmic polyadenylation element binding protein 1 (CPEB1) regulates NRF2 proteostasis and susceptibility to ferroptosis in pancreatic ductal adenocarcinoma (PDAC). We found that CPEB1 deficiency in cancer cells promotes the translation of p62/SQSTM1 by facilitating mRNA polyadenylation. Consequently, upregulated p62 enhances NRF2 stability by sequestering KEAP1, an E3 ligase for proteasomal degradation of NRF2, leading to the transcriptional activation of anti-ferroptosis genes. In support of the critical role of this signaling cascade in cancer therapy, CPEB1-deficient pancreatic cancer cells display higher resistance to ferroptosis-inducing agents than their CPEB1-normal counterparts in vitro and in vivo . Furthermore, based on the pathological evaluation of tissue specimens from 90 PDAC patients, we established that CPEB1 is an independent prognosticator whose expression level is closely associated with clinical therapeutic outcomes in PDAC. These findings identify the role of CPEB1 as a key ferroptosis regulator and a potential prognosticator in pancreatic cancer.

CPEB1 p62/SQSTM1 NRF2 pancreatic cancer ferroptosis

SCI

英语

第一 ; 通讯

National Natural Science Foundation of China["32170590","32070748"] ; Guangdong Province Department of Education[2021ZDZX2062] ; Shenzhen Science and Technology Innovation Commission[JCYJ2022053011 3814033] ; Excellent Scientific and Technological Innovation Training Program of Shenzhen[RCYX20210706092040048]

Biochemistry & Molecular Biology ; Life Sciences & Biomedicine - Other Topics

Biochemistry & Molecular Biology ; Biology

WOS:001247272500002

IVYSPRING INT PUBL

Web of Science

1.Southern Univ Sci & Technol, Key Univ Lab Metab & Hlth Guangdong, Sch Med, Biochem Dept, 1088 Xueyuan Ave, Shenzhen 518055, Guangdong, Peoples R China
2.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen Peoples Hosp, Dept Gastroenterol, 1017 Dongmen North Rd, Shenzhen 518020, Guangdong, Peoples R China
3.Southern Univ Sci & Technol, Dept Geriatr, 1017 Dongmen North Rd, Shenzhen 518020, Guangdong, Peoples R China
4.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen Peoples Hosp, Shenzhen Clin Res Ctr Geriatr, 1017 Dongmen North Rd, Shenzhen 518020, Guangdong, Peoples R China
5.Southern Univ Sci & Technol, Sch Med, 1088 Xueyuan Ave, Shenzhen 518055, Guangdong, Peoples R China
6.Southern Univ Sci & Technol Hosp, Clin Lab, 6019 Liuxian St,Xili Ave, Shenzhen 518055, Guangdong, Peoples R China
7.Beijing Tsinghua Changgung Hosp, 168 Litang Rd, Beijing 102218, Peoples R China
8.Tsinghua Univ, Sch Med, 168 Litang Rd, Beijing 102218, Peoples R China
9.Southern Univ Sci & Technol, Sch Med, Biochem Dept, 1088 Xueyuan Ave,Taizhou Bldg,Room 313, Shenzhen 518055, Guangdong, Peoples R China

Zhang, Shuxia,Huang, Jingnan,Lan, Zhangzhang,et al. CPEB1 Controls NRF2 Proteostasis and Ferroptosis Susceptibility in Pancreatic Cancer[J]. INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES,2024,20(8).

Zhang, Shuxia.,Huang, Jingnan.,Lan, Zhangzhang.,Xiao, Yanlin.,Liao, Youyou.,...&Du, Changzheng.(2024).CPEB1 Controls NRF2 Proteostasis and Ferroptosis Susceptibility in Pancreatic Cancer.INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES,20(8).

Zhang, Shuxia,et al."CPEB1 Controls NRF2 Proteostasis and Ferroptosis Susceptibility in Pancreatic Cancer".INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES 20.8(2024).