title: p62/SQSTM1 enhances breast cancer stem-like properties by stabilizing MYC mRNA.
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.
authors.affiliation: The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.|State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: L-Z
authors.initials: LZ
authors.lastname: Xu
authors.affiliation: The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.|State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: S-S
authors.initials: SS
authors.lastname: Li
authors.affiliation: The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.|State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: W
authors.initials: W
authors.lastname: Zhou
authors.affiliation: The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.|State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Z-J
authors.initials: ZJ
authors.lastname: Kang
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Q-X
authors.initials: QX
authors.lastname: Zhang
authors.affiliation: The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.|State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: M
authors.initials: M
authors.lastname: Kamran
authors.affiliation: The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.|State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.affiliation: The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.|State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: D-P
authors.initials: DP
authors.lastname: Liang
authors.affiliation: The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.|State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: C-L
authors.initials: CL
authors.lastname: Wang
authors.affiliation: The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.|State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Z-J
authors.initials: ZJ
authors.lastname: Hou
authors.affiliation: Department of Radiation Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: X-B
authors.initials: XB
authors.lastname: Wan
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Wang
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: E W-F
authors.initials: EW
authors.lastname: Lam
authors.affiliation: Department of Breast Surgery, The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Z-W
authors.initials: ZW
authors.lastname: Zhao
authors.affiliation: The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.|State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics*; D000071456:Sequestosome-1 Protein / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C489427:MYC protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C487931:mirnlet7 microRNA, human