Abstract
c-Myc, a key activator of cell proliferation and angiogenesis, promotes the development and progression of breast cancer. Ezrin-radixin-moesin-binding phosphoprotein-50 (EBP50) is a multifunctional scaffold protein that suppresses the proliferation of breast cancer cells. In this study we investigated whether the cancer-suppressing effects of EBP50 resulted from its regulation of c-Myc signaling in human breast cancer MCF-7 cells in vitro and in vivo. We first found a significant correlation between EBP50 and c-Myc expression levels in breast cancer tissue, and demonstrated that EBP50 suppressed cell proliferation through decreasing the expression of c-Myc and its downstream proteins cyclin A, E and Cdc25A in MCF-7 cells. We further showed that EBP50 did not regulate c-Myc mRNA expression, but it promoted the degradation of c-Myc through the autophagic lysosomal pathway. Moreover, EBP50 promoted integration between c-Myc and p62, an autophagic cargo protein, triggering the autophagic lysosomal degradation of c-Myc. In EBP50-silenced MCF-7 cells, activation of autophagy by Beclin-1 promoted the degradation of c-Myc and inhibited cell proliferation. These results demonstrate that the EBP50/Beclin-1/p62/c-Myc signaling pathway plays a role in the proliferation in MCF-7 breast cancer cells: EBP50 stimulates the autophagic lysosomal degradation of c-Myc, thereby inhibits the proliferation of MCF-7 cells. Based on our results, promoting the lysosomal degradation of c-Myc might be a promising new strategy for treating breast cancer.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Vaquero J, Nguyen Ho-Bouldoires TH, Claperon A, Fouassier L. Role of the PDZ-scaffold protein NHERF1/EBP50 in cancer biology: from signaling regulation to clinical relevance. Oncogene 2017; 36: 3067–79.
Liu H, Ma Y, He HW, Wang JP, Jiang JD, Shao RG. SLC9A3R1 stimulates autophagy via BECN1 stabilization in breast cancer cells. Autophagy 2015; 11: 2323–34.
Yao W, Feng D, Bian W, Yang L, Li Y, Yang Z, et al. EBP50 inhibits EGF-induced breast cancer cell proliferation by blocking EGFR phosphorylation. Amino Acids 2012; 43: 2027–35.
Pan Y, Wang L, Dai JL. Suppression of breast cancer cell growth by Na+/H+ exchanger regulatory factor 1 (NHERF1). Breast Cancer Res 2006; 8: R63.
Wade MA, Sunter NJ, Fordham SE, Long A, Masic D, Russell LJ, et al. c-MYC is a radiosensitive locus in human breast cells. Oncogene 2015; 34: 4985–94.
Green AR, Aleskandarany MA, Agarwal D, Elsheikh S, Nolan CC, Diez-Rodriguez M, et al. MYC functions are specific in biological subtypes of breast cancer and confers resistance to endocrine therapy in luminal tumours. Br J Cancer 2016; 114: 917–28.
Xu J, Chen Y, Olopade OI. MYC and breast cancer. Genes Cancer 2010; 1: 629–40.
Albajar M, Gomez-Casares MT, Llorca J, Mauleon I, Vaque JP, Acosta JC, et al. MYC in chronic myeloid leukemia: induction of aberrant DNA synthesis and association with poor response to imatinib. Mol Cancer Res 2011; 9: 564–76.
Miller DM, Thomas SD, Islam A, Muench D, Sedoris K. c-Myc and cancer metabolism. Clin Cancer Res 2012; 18: 5546–53.
Herranz D, Maraver A, Canamero M, Gomez-Lopez G, Inglada-Perez L, Robledo M, et al. SIRT1 promotes thyroid carcinogenesis driven by PTEN deficiency. Oncogene 2013; 32: 4052–6.
Hubbard GK, Mutton LN, Khalili M, McMullin RP, Hicks JL, Bianchi-Frias D, et al. Combined MYC activation and Pten loss are sufficient to create genomic instability and lethal metastatic prostate cancer. Cancer Res 2016; 76: 283–92.
Liu H, Ma Y, He HW, Zhao WL, Shao RG. SPHK1 (sphingosine kinase 1) induces epithelial-mesenchymal transition by promoting the autophagy-linked lysosomal degradation of CDH1/E-cadherin in hepatoma cells. Autophagy 2017; 13: 900–13.
Yan LX, Wu QN, Zhang Y, Li YY, Liao DZ, Hou JH, et al. Knockdown of miR-21 in human breast cancer cell lines inhibits proliferation, in vitro migration and in vivo tumor growth. Breast Cancer Res 2011; 13: R2.
Zheng JF, Sun LC, Liu H, Huang Y, Li Y, He J. EBP50 exerts tumor suppressor activity by promoting cell apoptosis and retarding extracellular signal-regulated kinase activity. Amino Acids 2010; 38: 1261–8.
Zhang Y, Wang Z, Li X, Magnuson NS. Pim kinase-dependent inhibition of c-Myc degradation. Oncogene 2008; 27: 4809–19.
Jing H, Hu J, He B, Negron Abril YL, Stupinski J, Weiser K, et al. A SIRT2-selective inhibitor promotes c-Myc oncoprotein degradation and exhibits broad anticancer activity. Cancer Cell 2016; 29: 767–8.
Yu Z, Li T, Wang C, Deng S, Zhang B, Huo X, et al. Gamabufotalin triggers c-Myc degra–dation via induction of WWP2 in multiple myeloma cells. Oncotarget 2016; 7: 1572537.
Pei Y, Yao Q, Yuan S, Xie B, Liu Y, Ye C, et al. GATA4 promotes hepatoblastoma cell proliferation by altering expression of miR125b and DKK3. Oncotarget 2016; 7: 77890–901.
Kang C, Xu Q, Martin TD, Li MZ, Demaria M, Aron L, et al. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science 2015; 349: aaa5612.
Cianfanelli V, Fuoco C, Lorente M, Salazar M, Quondamatteo F, Gherardini PF, et al. AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation. Nat Cell Biol 2015; 17: 20–30.
Puustinen P, Rytter A, Mortensen M, Kohonen P, Moreira JM, Jaattela M. CIP2A oncoprotein controls cell growth and autophagy through mTORC1 activation. J Cell Biol 2014; 204: 713–27.
Gomes LR, Menck CFM, Cuervo AM. Chaperone-mediated autophagy prevents cellular transformation by regulating MYC proteasomal degradation. Autophagy 2017; 13: 928–40.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (31401186, 81473249, 81321004 and 81673471), National Mega-project for Innovative Drugs (2014ZX09201042) and the CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-2-002).
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Supplementary Figure 1
Statistical analysis of cells per field in Figure 1C.
Supplementary Figure 2
EBP50 reduces the proliferation of MCF-7 cells.
Rights and permissions
About this article
Cite this article
Liu, H., Zhao, Wl., Wang, Jp. et al. EBP50 suppresses the proliferation of MCF-7 human breast cancer cells via promoting Beclin-1/p62-mediated lysosomal degradation of c-Myc. Acta Pharmacol Sin 39, 1347–1358 (2018). https://doi.org/10.1038/aps.2017.171
Received:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/aps.2017.171
Keywords
This article is cited by
-
Molecular heterogeneity and MYC dysregulation in triple-negative breast cancer: genomic advances and therapeutic implications
3 Biotech (2025)
-
Deubiquitination of CDC6 by OTUD6A promotes tumour progression and chemoresistance
Molecular Cancer (2024)
-
c-MYC mediates the crosstalk between breast cancer cells and tumor microenvironment
Cell Communication and Signaling (2023)
