Sorting nexin 10 acts as a tumor suppressor in tumorigenesis and progression of colorectal cancer through regulating chaperone mediated autophagy degradation of p21Cip1/WAF1. (10th April 2018)

• Record Type: Journal Article
• Authors: Zhang, Sulin; Hu, Bin; You, Yan; Yang, Zhiwen; Liu, Lixin; Tang, Huanhuan; Bao, Weilian; Guan, Yunyun; Shen, Xiaoyan
• Is Part Of: Cancer letters. Volume 419(2018)
• Page Start: 116
• Page End: 127
• Publication Date: 2018-04-10
• Subjects: SNX10 -- Chaperone-mediated autophagy -- Colorectal cancer -- p21Cip1/WAF1; SNX10 sorting nexin 10 -- CRC colorectal cancer -- CMA chaperone mediated autophagy -- EBSS Earle's balanced salt solution -- CQ chloroquine -- LAMP-1 lysosomal-associated membrane protein 1 -- LAMP-2A lysosomal-associated membrane protein type 2A -- Hsc70 heat shock cognate protein 70 -- GAPDH glyceraldehyde-3-phosphate dehydrogenase -- RT-qPCR real time quantitative polymerase chain reaction -- mRNA messenger RNA -- SiRNA Small interfering RNA -- WT wild type -- KO knockout -- IP immunoprecipitation -- SOP nanoparticles encapsulated SNX10-Flag -- MP mock nanoparticles; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.01.045
• Languages: English
• ISSNs: 0304-3835

Abstract

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 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/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. Highlights: SNX10 knockout increases activation of CMA by preventing the degradation of LAMP-2A. p21 Cip1/WAF1 is a putative substrate of CMA in HCT116 cells. Degradation of p21 by CMA contributes to CRC cell proliferation and survival. SNX10 deficiency promotes tumorigenesis and progression of colorectal cancer. SNX10 is decreased in human CRC tissues which show increased CMA and reduced P21