Menin inhibition suppresses castration-resistant prostate cancer and enhances chemosensitivity

Chaïma Cherif,Martin Gleave,Abdessamad El Kaoutari,Thibaud Sefiane,Palma Rocchi,Philippe Barthélémy,Julien Vernerey,Clément Paris,Thi Khanh Le,David Taïeb,Mohamed Manai,Nadine Carbuccia,Pascal Finetti,Dang Tan Nguyen,Ladan Fazli,Daniel Birnbaum,Max Chaffanet,François Bertucci

doi:10.1038/s41388-021-02039-2

Abstract

Disease progression and therapeutic resistance of prostate cancer (PC) are linked to multiple molecular events that promote survival and plasticity. We previously showed that heat shock protein 27 (HSP27) acted as a driver of castration-resistant phenotype (CRPC) and developed an oligonucleotides antisense (ASO) against HSP27 with evidence of anti-cancer activity in men with CRPC. Here, we show that the tumor suppressor Menin (MEN1) is highly regulated by HSP27. Menin is overexpressed in high-grade PC and CRPC. High MEN1 mRNA expression is associated with decreased biochemical relapse-free and overall survival. Silencing Menin with ASO technology inhibits CRPC cell proliferation, tumor growth, and restores chemotherapeutic sensitivity. ChIP-seq analysis revealed differential DNA binding sites of Menin in various prostatic cells, suggesting a switch from tumor suppressor to oncogenic functions in CRPC. These data support the evaluation of ASO against Menin for CRPC.

Highlights

Prostate cancer (PC) is one of the most common cancers in European and American countries
To obtain a large-scale overview of heat shock protein 27 (HSP27)-regulated proteins driving castration-resistant PC (CRPC), we performed a proteomic analysis in CRPC LNCaP-HSP27 [3] and castration-sensitive prostate cancer (CSPC) LNCaP-Mock models
Because it is the most highly regulated pathway, we focused our attention on the “transcriptional misregulation in cancer pathway”, containing three identified proteins (DEAD-Box Helicase 5, DDX5; eyes absent 1 protein, EYA1, and Menin) present in CRPC model (LNCaP-HSP27) and not detected in CSPC model (LNCaP-Mock)

Summary

Introduction

Prostate cancer (PC) is one of the most common cancers in European and American countries. Most of the metastatic patients will initially respond to androgen deprivation therapy (ADT). The disease will progress after several years to castration-resistant PC (CRPC), which remains a challenging therapeutic situation for clinicians [1]. We identified the stress-activated cytoprotective chaperone heat shock protein 27 (HSP27) to be highly overexpressed in CRPC, supporting tumor cell survival and plasticity via various pathways. We described a wide diversity of new HSP27 functions that can play critical roles in PC tumorigenesis and therapeutic resistance [5]. We found that HSP27 regulates its protein partner expression at the posttranslational level, such as the eukaryotic initiation factor 4E (eIF4E) and translationally controlled tumor protein (TCTP), which were demonstrated to be rapidly ubiquitinated and degraded by the proteasome in HSP27 absence [6, 7]

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