Hsp90B enhances MAST1-mediated cisplatin resistance by protecting MAST1 from proteosomal degradation
Chaoyun Pan, … , Lingtao Jin, Sumin Kang
Chaoyun Pan, … , Lingtao Jin, Sumin Kang
Published August 26, 2019
Citation Information: J Clin Invest. 2019;129(10):4110-4123. https://doi.org/10.1172/JCI125963.
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Research Article Oncology Therapeutics

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

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.

Authors

Chaoyun Pan, Jaemoo Chun, Dan Li, Austin C. Boese, Jie Li, JiHoon Kang, Anna Umano, Yunhan Jiang, Lina Song, Kelly R. Magliocca, Zhuo G. Chen, Nabil F. Saba, Dong M. Shin, Taofeek K. Owonikoko, Sagar Lonial, Lingtao Jin, Sumin Kang

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Figure 6

CHIP degrades MAST1, which consequently sensitizes cisplatin-resistant cells to cisplatin.

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CHIP degrades MAST1, which consequently sensitizes cisplatin-resistant c...
(A) Effect of CHIP overexpression and MAST1 knockdown on cisplatin sensitivity and MAST1 protein level. (B) Effect of MAST1 WT rescue expression on cisplatin sensitivity and MAST1 protein level in cells with CHIP overexpression and MAST1 knockdown. (C) Effect of CHIP and MAST1 WT or 2KR overexpression on cisplatin sensitivity and MAST1 protein level. KB-3-1cisR and A549cisR cells with flag-CHIP and MAST1 knockdown or WT/2KR overexpression were treated with increasing concentrations of cisplatin in the presence of 17-AAG for 48 hours. Cell viability was determined by CellTiter-Glo assay. Data are mean ± SD from 3 technical replicates and representative of 4 (A) and 2 (B and C) independent biological experiments. Statistical analysis was performed by 1-way ANOVA. ***P < 0.005; ****P < 0.0001.