2. Academic Validation
  3. HSPA8 Activates Wnt/β-Catenin Signaling to Facilitate BRAF V600E Colorectal Cancer Progression by CMA-Mediated CAV1 Degradation

HSPA8 Activates Wnt/β-Catenin Signaling to Facilitate BRAF V600E Colorectal Cancer Progression by CMA-Mediated CAV1 Degradation

  • Adv Sci (Weinh). 2023 Nov 16:e2306535. doi: 10.1002/advs.202306535.
Bowen Li 1,  Hui Ming 1,  Siyuan Qin 1,  Li Zhou 1,  Zhao Huang 1,  Ping Jin 1,  Liyuan Peng 1,  Maochao Luo 1,  Tingting Zhang 1,  Kui Wang 1,  Rui Liu 2,  Yih-Cherng Liou 3 4,  Edouard C Nice 5,  Jingwen Jiang 6,  Canhua Huang 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China.
  • 2 State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, P. R. China.
  • 3 Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 117543, Singapore.
  • 4 Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, 117573, Singapore.
  • 5 Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia.
  • 6 West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, 610041, P. R. China.
PMID: 37973552 DOI: 10.1002/advs.202306535
Abstract

BRaf V600E attracts wide attention in the treatment of colorectal Cancer (CRC) as stratifying and predicting a refractory classification of CRC. Recent evidence indicates that Wnt/β-catenin signaling is broadly activated and participates in the refractoriness of BRaf V600E CRC, but the underlying molecular mechanism needs to be elucidated. Here, heat shock 70 kDa protein 8 (HSPA8), an essential regulator in chaperone-mediated Autophagy (CMA), is identified as a potential therapeutic target for advanced BRaf V600E CRC. These results show that HSPA8 is transcriptionally upregulated in BRaf V600E CRC, which promotes CMA-dependent degradation of caveolin-1 (CAV1) to release β-catenin into the nucleus and thus activates the Wnt/β-catenin pathway, contributing to metastasis and progression of BRaf V600E CRC. Of note, HSPA8 directly interacts with the KIFSN motif on CAV1, the interaction can be enhanced by p38 MAPK-mediated CAV1 S168 phosphorylation. Furthermore, pharmacological targeting HSPA8 by VER155008 exhibits synergistic effects with BRaf inhibitors on CRC mouse models. In summary, these findings discover the important role of the HSPA8/CAV1/β-catenin axis in the development of refractory BRaf V600E CRC and highlight HSPA8 as a predictive biomarker and therapeutic target in clinical practice.

Keywords

BRAF V600E; Wnt/β-catenin; drug resistance; epithelial-mesenchymal transition; heat shock 70 kDa protein 8.

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