Intestinal Apc-inactivation induces HSP25 dependency

The majority of colorectal cancers (CRCs) present with early mutations in tumour suppressor gene APC. APC mutations result in oncogenic activation of the Wnt pathway, which is associated with hyperproliferation, cytoskeletal remodelling 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.

大多数结直肠癌（colorectal cancers, CRCs）在肿瘤抑制基因APC中存在早期突变。APC突变会导致Wnt通路（Wnt pathway）的致癌性激活，该通路与细胞过度增殖、细胞骨架重塑以及mRNA翻译的整体上调密切相关。为弥补生物合成需求的增加，癌细胞主要依赖分子伴侣蛋白（protein chaperones）来维持蛋白质稳态（proteostasis），不过这类蛋白在结直肠癌中的功能仍未得到充分探索。为探究分子伴侣蛋白在驱动结直肠癌发生中的作用，我们获取了处于活跃转化阶段的野生型与Apc突变型小鼠类器官的转录组谱。我们发现编码小热休克蛋白25（small heat shock protein 25, HSP25）的Hspb1基因出现了显著的转录上调。通过体外类器官培养与小鼠模型实验，我们证实了HSP25在促进Apc介导的肿瘤转化中发挥不可或缺的作用；同时证明使用溴夫定（brivudine）对HSP25进行化学抑制，能够降低癌前腺瘤的发生发展。本研究揭示了肠道转化过程中此前未被认知的易感靶点，该靶点可用于开发针对高危人群的化学预防策略。