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 p21(Cip1/WAF1). a master effector in various tumor suppressor pathways, is a substrate of CMA, and decrease of p21(Cip1/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 p21(Cip1/lWAF1). 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. (C) 2018 Elsevier B.V. All rights reserved.
[1]Fudan Univ, Sch Pharm, Dept Pharmacol, 826 Zhangheng Rd, Shanghai 201203, Peoples R China.
[2]Shanghai Jiao Tong Univ, Affiliated Shanghai Peoples Hosp 1, Songjiang Hosp, Dept Pharm, Shanghai, Peoples R China.
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