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Intestinal Apc‐inactivation induces HSP25 dependency

Authors :
Sanne M van Neerven
Wouter L Smit
Milou S van Driel
Vaishali Kakkar
Nina E de Groot
Lisanne E Nijman
Clara C Elbers
Nicolas Léveillé
Jarom Heijmans
Louis Vermeulen
Source :
EMBO Molecular Medicine, Vol 14, Iss 12, Pp 1-16 (2022)
Publication Year :
2022
Publisher :
Springer Nature, 2022.

Abstract

Abstract The majority of colorectal cancers (CRCs) present with early mutations in tumor suppressor gene APC. APC mutations result in oncogenic activation of the Wnt pathway, which is associated with hyperproliferation, cytoskeletal remodeling, and a global increase in mRNA translation. To compensate for the increased biosynthetic demand, cancer cells critically depend on protein chaperones to maintain proteostasis, although their function in CRC remains largely unexplored. In order to investigate the role of molecular chaperones in driving CRC initiation, we captured the transcriptomic profiles of murine wild type and Apc‐mutant organoids during active transformation. We discovered a strong transcriptional upregulation of Hspb1, which encodes small heat shock protein 25 (HSP25). We reveal an indispensable role for HSP25 in facilitating Apc‐driven transformation, using both in vitro organoid cultures and mouse models, and demonstrate that chemical inhibition of HSP25 using brivudine reduces the development of premalignant adenomas. These findings uncover a hitherto unknown vulnerability in intestinal transformation that could be exploited for the development of chemopreventive strategies in high‐risk individuals.

Details

Language :
English
ISSN :
17574676 and 17574684
Volume :
14
Issue :
12
Database :
Directory of Open Access Journals
Journal :
EMBO Molecular Medicine
Publication Type :
Academic Journal
Accession number :
edsdoj.891ee3363d044458ba63925b9b465371
Document Type :
article
Full Text :
https://doi.org/10.15252/emmm.202216194