p62/SQSTM1 enhances breast cancer stem-like properties by stabilizing MYC mRNA

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Title: p62/SQSTM1 enhances breast cancer stem-like properties by stabilizing MYC mRNA
Authors: Xu, LZ
Li, SS
Zhou, W
Kang, ZJ
Zhang, QX
Kamran, M
Xu, J
Liang, DP
Wang, CL
Hou, ZJ
Wan, XB
Lam, EW
Zhao, ZW
Liu, Q
Item Type: Journal Article
Abstract: Aberrant p62 overexpression has been implicated in breast cancer development. Here, we found that p62 expression was elevated in breast cancer stem cells (BCSCs), including CD44+CD24− fractions, mammospheres, ALDH1+ populations and side population cells. Indeed, short-hairpin RNA (shRNA)-mediated knockdown of p62 impaired breast cancer cells from self-renewing under anchorage-independent conditions, whereas ectopic overexpression of p62 enhanced the self-renewal ability of breast cancer cells in vitro. Genetic depletion of p62 robustly inhibited tumor-initiating frequencies, as well as growth rates of BCSC-derived tumor xenografts in immunodeficient mice. Consistently, immunohistochemical analysis of clinical breast tumor tissues showed that high p62 expression levels were linked to poorer clinical outcome. Further gene expression profiling analysis revealed that p62 was positively correlated with MYC expression level, which mediated the function of p62 in promoting breast cancer stem-like properties. MYC mRNA level was reduced upon p62 deletion by siRNA and increased with p62 overexpression in breast cancer cells, suggesting that p62 positively regulated MYC mRNA. Interestingly, p62 did not transactivate MYC promoter. Instead, p62 delayed the degradation of MYC mRNA by repressing the expression of let-7a and let-7b, thus promoting MYC mRNA stabilization at the post-transcriptional level. Consistently, let-7a and let-7b mimics attenuated p62-mediated MYC mRNA stabilization. Together, these findings unveiled a previously unappreciated role of p62 in the regulation of BCSCs, assigning p62 as a promising therapeutic target for breast cancer treatments.
Issue Date: 27-Jun-2016
Date of Acceptance: 11-Apr-2016
ISSN: 1476-5594
Publisher: Nature Publishing Group
Start Page: 304
End Page: 317
Journal / Book Title: Oncogene
Volume: 36
Copyright Statement: © 2016 Macmillan Publishers Limited. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit
Sponsor/Funder: Biotechnology and Biological Sciences Research Council (BBSRC)
Cancer Research UK
Breast Cancer Now
Breast Cancer Now
Funder's Grant Number: BBS/B/03785
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
Genetics & Heredity
1112 Oncology And Carcinogenesis
1103 Clinical Sciences
Oncology & Carcinogenesis
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine

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