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Cancer Lett. 2018 Apr 10;419:116-127. doi: 10.1016/j.canlet.2018.01.045.

Sorting nexin 10 acts as a tumor suppressor in tumorigenesis and progression of colorectal cancer through regulating chaperone mediated autophagy degradation of p21Cip1/WAF1.

Author information

1
Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
2
Department of Pharmacy, Songjiang Hospital Affiliated Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
3
Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China. Electronic address: shxiaoy@fudan.edu.cn.

Abstract

Chaperone-mediated autophagy (CMA) characterized by the selective degradation of target proteins has been linked with tumorigenesis in recent years. Here, we explored the function of sorting nexin 10 (SNX10), a protein involved in maintaining endosome/lysosome homeostasis, in mediating CMA activity and its impact on the progression of mouse inflammation-driven colorectal cancer. Our results revealed that SNX10 deficiency increased the activation of CMA by preventing the degradation of lysosomal LAMP-2A. In SNX10 KO cells, we disclosed that p21Cip1/WAF1, a master effector in various tumor suppressor pathways, is a substrate of CMA, and decrease of p21Cip1/WAF1 caused by SNX10-mediated CMA activation contributes to HCT116 cell proliferation and survival. Moreover, we found that SNX10 KO promoted tumorigenesis in the mouse colorectum which could be restored by SNX10 over-expression. Furthermore, SNX10 was remarkably down-regulated in human CRC tissues which showed the increased activity of CMA and decreased expression of p21Cip1/WAF1. These findings suggest that SNX10 acts as a tumor suppressor in the mouse colorectum and drives inflammation-associated colorectal cancer by a chaperone-mediated autophagy mechanism.

KEYWORDS:

Chaperone-mediated autophagy; Colorectal cancer; SNX10; p21(Cip1/WAF1)

PMID:
29355659
DOI:
10.1016/j.canlet.2018.01.045
[Indexed for MEDLINE]

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