Hsp90B enhances MAST1-mediated cisplatin resistance by protecting MAST1 from proteosomal degradation

• Type of Material: Article
• Authors: Chaoyun Pan, Emory University; Jaemoo Chun, Emory University; Dan Li, Emory University; Austin C. Boese, Emory University; Jie Li, Emory University; JiHoon Kang, Emory University; Anna Umano, Emory University; Yunhan Jiang, Emory University; Lina Song, Emory University; Kelly Magliocca, Emory University; Zhuo G. Chen, Emory University; Nabil Saba, Emory University; Dong Shin, Emory University; Taofeek Owonikoko, Emory University; Sagar Lonial, Emory University; Lingtao Jin, Emory University; Sumin Kang, Emory University
• Language: English
• Date: 2019-10-01
• Publisher: AMER SOC CLINICAL INVESTIGATION INC
• Publication Version: Final Published Version
• Copyright Statement: © 2019, American Society for Clinical Investigation.
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI125963
• Title of Journal or Parent Work: JOURNAL OF CLINICAL INVESTIGATION
• Volume: 129
• Issue: 10
• Start Page: 4110
• End Page: 4123
• Grant/Funding Information: SK is a Robbins Scholar, a Georgia Cancer Coalition Scholar, and an American Cancer Society Basic Research Scholar.; This study was supported by NIH grants R01 CA207768 and R01 CA175316 (to SK), Department of Defense grant W81XWH-17-1-0186 (to SK), Developmental Funds from the Winship Cancer Institute of Emory University (to SK), Winship IRG-17-181-04 from the American Cancer Society (to LJ), the 2019 Breast Cancer Research Foundation-AACR Career Development Awards for Translational Breast Cancer Research 19-20-26-JIN (to LJ), an Elsa U. Pardee Foundation grant (to LJ), and a UF Health Cancer Center pilot grant (to LJ).
• Keywords: INHIBITION; PROTEIN; DRUG-RESISTANCE; CHIP; Life Sciences & Biomedicine; PROTEASOMAL DEGRADATION; Science & Technology; MOLECULAR-MECHANISMS; CANCER; Medicine, Research & Experimental; CHAPERONE; COMPLEX; Research & Experimental Medicine; EXPERIMENTAL-DESIGN
• Research Categories: Chemistry, Pharmaceutical; Health Sciences, Oncology

Abstract

Microtubule-associated serine/threonine kinase 1 (MAST1) is a central driver of cisplatin resistance in human cancers. However, the molecular mechanism regulating MAST1 levels in cisplatin-resistant tumors is unknown. Through a proteomics screen, we identified the heat shock protein 90 B (hsp90B) chaperone as a direct MAST1 binding partner essential for its stabilization. Targeting hsp90B sensitized cancer cells to cisplatin predominantly through MAST1 destabilization. Mechanistically, interaction of hsp90B with MAST1 blocked ubiquitination of MAST1 at lysines 317 and 545 by the E3 ubiquitin ligase CHIP and prevented proteasomal degradation. The hsp90B-MAST1-CHIP signaling axis and its relationship with cisplatin response were clinically validated in cancer patients. Furthermore, combined treatment with a hsp90 inhibitor and the MAST1 inhibitor lestaurtinib further abrogated MAST1 activity and consequently enhanced cisplatin-induced tumor growth arrest in a patient-derived xenograft model. Our study not only uncovers the regulatory mechanism of MAST1 in tumors but also suggests a promising combinatorial therapy to overcome cisplatin resistance in human cancers.