Intestinal Apc ‐inactivation induces HSP25 dependency

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. image Upon loss of Apc , the most common early genetic lesion in colorectal cancer, cells upregulate a genetic program involved in buffering proteotoxic stress, including small heat shock protein HSP25. Here, we reveal that inhibition of HSP25 inhibits oncogenic transformation and prevents polyp formation. Intestinal epithelial loss of Apc instructs a Wnt‐driven program for oncogenic transformation that includes the small heat shock protein and chaperone HSP25. Genetic deletion or chemical inhibition of HSP25 using brivudine inhibits transformation and clonal expansion of murine and human APC ‐mutant organoids in vitro . Oral administration of brivudine prevents oncogenic transformation and adenoma development in vivo , underscoring the essential role of HSP25 in early tumor formation. This study provides rationale for HSP25 inhibition as a chemoprevention strategy for patients with familial adenomatous polyposis that carry germline mutations in the APC gene.