iASPP Is an Antioxidative Factor and Drives Cancer Growth and Drug Resistance by Competing with Nrf2 for Keap1 Binding

Wenjie Ge; Kunming Zhao; Xingwen Wang; Huayi Li; Miao Yu; Mengmeng He; Xuting Xue; Yifu Zhu; Cheng Zhang; Yiwei Cheng; Shijian Jiang; Ying Hu

doi:10.1016/j.ccell.2017.09.008

iASPP Is an Antioxidative Factor and Drives Cancer Growth and Drug Resistance by Competing with Nrf2 for Keap1 Binding

Cancer Cell. 2017 Nov 13;32(5):561-573.e6. doi: 10.1016/j.ccell.2017.09.008. Epub 2017 Oct 12.

Authors

Wenjie Ge¹, Kunming Zhao¹, Xingwen Wang¹, Huayi Li¹, Miao Yu², Mengmeng He¹, Xuting Xue¹, Yifu Zhu¹, Cheng Zhang³, Yiwei Cheng³, Shijian Jiang¹, Ying Hu⁴

Affiliations

¹ School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province 150001, China.
² School of Chemistry, Harbin Institute of Technology, Harbin, Heilongjiang Province 150001, China.
³ Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150006, China.
⁴ School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province 150001, China; Shenzhen Graduate School of Harbin Institute of Technology, Shenzhen 518055, China. Electronic address: huying@hit.edu.cn.

PMID: 29033244
DOI: 10.1016/j.ccell.2017.09.008

Abstract

Reactive oxygen species (ROS) have emerged as important signaling molecules that play crucial roles in carcinogenesis and cytotoxic responses. Nrf2 is the master regulator of ROS balance. Thus, uncovering mechanisms of Nrf2 regulation is important for the development of alternative treatment strategies for cancers. Here, we demonstrate that iASPP, a known p53 inhibitor, lowers ROS independently of p53. Mechanistically, iASPP competes with Nrf2 for Keap1 binding via a DLT motif, leading to decreased Nrf2 ubiquitination and increased Nrf2 accumulation, nuclear translocation, and antioxidative transactivation. This iASPP-Keap1-Nrf2 axis promotes cancer growth and drug resistance both in vitro and in vivo. Thus, iASPP is an antioxidative factor and represents a promising target to improve cancer treatment, regardless of p53 status.

Keywords: Keap1; Nrf2; ROS; cancer growth; chemoresistance; iASPP; renal cell carcinoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antioxidants / metabolism
Blotting, Western
Cell Line, Tumor
Cell Proliferation*
Drug Resistance, Neoplasm*
HCT116 Cells
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Kelch-Like ECH-Associated Protein 1 / genetics
Kelch-Like ECH-Associated Protein 1 / metabolism*
NF-E2-Related Factor 2 / genetics
NF-E2-Related Factor 2 / metabolism*
Neoplasms / genetics
Neoplasms / metabolism
Neoplasms / pathology
Protein Binding
RNA Interference
Reactive Oxygen Species / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism*
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism

Substances

Antioxidants
Intracellular Signaling Peptides and Proteins
KEAP1 protein, human
Kelch-Like ECH-Associated Protein 1
NF-E2-Related Factor 2
NFE2L2 protein, human
PPP1R13L protein, human
Reactive Oxygen Species
Repressor Proteins
Tumor Suppressor Protein p53