Targeting Cul3-scaffold E3 ligase complex via KLHL substrate adaptors for cancer therapy

Senfeng Xiang; Xiaoxian Shi; Pengfei Chen; Yifan Chen; Shaowei Bing; Xizhi Jin; Ji Cao; Jinhu Wang; Bo Yang; Xuejing Shao; Qiaojun He; Meidan Ying

doi:10.1016/j.phrs.2021.105616

Targeting Cul3-scaffold E3 ligase complex via KLHL substrate adaptors for cancer therapy

Pharmacol Res. 2021 Jul:169:105616. doi: 10.1016/j.phrs.2021.105616. Epub 2021 Apr 17.

Authors

Senfeng Xiang¹, Xiaoxian Shi¹, Pengfei Chen¹, Yifan Chen¹, Shaowei Bing¹, Xizhi Jin¹, Ji Cao², Jinhu Wang³, Bo Yang², Xuejing Shao⁴, Qiaojun He⁵, Meidan Ying⁶

Affiliations

¹ Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
² Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Cancer Center of Zhejiang University, Hangzhou 310058, China.
³ Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China; Cancer Center of Zhejiang University, Hangzhou 310058, China.
⁴ Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: xjshao@zju.edu.cn.
⁵ Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Cancer Center of Zhejiang University, Hangzhou 310058, China; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310058, China; Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China. Electronic address: qiaojunhe@zju.edu.cn.
⁶ Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China; Cancer Center of Zhejiang University, Hangzhou 310058, China. Electronic address: mying@zju.edu.cn.

PMID: 33872809
DOI: 10.1016/j.phrs.2021.105616

Abstract

Targeted therapy has become increasingly important and indispensable in cancer therapy. Cullin3-RING ligases (CRL3) serve as essential executors for regulating protein homeostasis in cancer development, highlighting that CRL3 might be promising targets in various cancer treatment. However, how to design new targeted therapies by disrupting the function of CRL3 is poorly understood. Here, we focus on the substrate adaptors of CRL3, and carry out a systematical research on the function of Kelch-like (KLHL) family proteins. We have identified twenty-four KLHL proteins with function of tumor promotion and thirteen KLHL proteins with high clinical significance on cancer therapy. Furthermore, we have clarified the novel biological function of KLHL13 as a vital factor that contributes to malignant progression in lung cancer. Taken together, our findings reveal multiple potential therapeutical targets and provide evidence for targeting CRL3 via KLHL substrate adaptors for cancer therapy.

Keywords: Cancer therapy; Cullin3-RING Ligase; KLHL; Substrate adaptor; Target discovery.

Publication types

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

MeSH terms

Cell Line, Tumor
Colonic Neoplasms / drug therapy
Colonic Neoplasms / metabolism
Cullin Proteins / metabolism*
Female
Humans
Kelch Repeat*
Lung Neoplasms / drug therapy
Lung Neoplasms / metabolism
Molecular Targeted Therapy / methods*
Neoplasm Proteins / metabolism*
Neoplasms / drug therapy
Neoplasms / metabolism*
Neoplasms / pathology
Ovarian Neoplasms / drug therapy
Ovarian Neoplasms / metabolism
Ubiquitin-Protein Ligases / metabolism*

Substances

CUL3 protein, human
Cullin Proteins
Neoplasm Proteins
Ubiquitin-Protein Ligases