X-linked inhibitor of apoptosis protein (XIAP) possesses a critical role in promotion of cell survival and maintenance of cellular homeostasis. In cancer, elevated XIAP expression has been associated with malignancy, poor prognosis, and treatment resistance. However, the underlying mechanisms of these effects remain unclear. XIAP has previously been proposed to promote tumor growth through suppression of autophagy. In this study, we examined the expression of XIAP and p62, two critical mediators of autophagy, in breast and colon cancer. We observed a negative correlation between XIAP and p62 expression in normal and cancer tissues of breast and colon, and that the ratio of XIAP and p62 expression determines the cancer phenotype. In vitro, we observed that XIAP interacted with p62 and also that XIAP depletion resulted in increased expression of p62. XIAP functioned as an ubiquitination E3 ligase towards p62 and suppressed p62 expression through ubiquitin–proteasomal degradation. Furthermore, XIAP enhanced cancer cell proliferation, viability, and colony formation in vitro via suppression of p62. In addition, we demonstrated that XIAP-enhanced tumor growth is dependent on depletion of p62 in vivo. Herein, we have therefore delineated a novel mechanism by which XIAP contributes to development and progression of breast and colon carcinoma.
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These authors contributed equally: Xing Huang, Xiao-nan Wang
We deeply thank Dr. Bert Vogelstein (Johns Hopkins University) for XIAP−/− HCT116 and XIAP−/− DLD1 cell lines, Dr. Noboru Mizushima (The University of Tokyo) for Atg5−/− MEF cell lines, and Dr. Tao Zhu (University of Science & Technology of China) for breast cell lines. Especially, the author Xing Huang would like to express deepest thanks to Dr. Mian Wu (University of Science & Technology of China) for the technological training and ideological inspiration in his lab. This work was supported by grants from National Natural Science Foundation of China (81502975, 81472493, and 81572305), and China Postdoctoral Science Foundation (2016T90413 and 2015M581693). The research was funded in part by Jiangsu Planned Projects for Postdoctoral Research Funds (1501002A), Fundamental Research Funds for the Central Universities (2242016R20027 and 2242016K41045), Anhui provincial academic and technical leader reserve candidate (#2016H074), Key Program of Outstanding Young Talents in Higher Education Institutions of Anhui (#gxyqZD2016046) and the Shenzhen Development and Reform Commission Subject Construction Project (1434).
X.H. and Z.W. conceived the project, designed, and conducted the majority of the experiments, with the assistance from X.-n.W., X.-d.Y., and W.-y.W. X.H., P.E.L., and Z.W. performed the data analysis and interpretation. X.H., X.-d.Y., P.E.L., and Z.W. wrote the manuscript; other authors discussed the results and commented on the manuscript. X.H. and Z.W. supervised the study.