A miRNA-HERC4 pathway promotes breast tumorigenesis by inactivating tumor suppressor LATS1

Abstract

The E3 ligase HERC4 is overexpressed in human breast cancer and its expression levels correlated with the prognosis of breast cancer patients. However, the roles of HERC4 in mammary tumorigenesis remain unclear. Here we demonstrate that the knockdown of HERC4 in human breast cancer cells dramatically suppressed their proliferation, survival, migration, and tumor growth in vivo, while the overexpression of HERC4 promoted their aggressive tumorigenic activities. HERC4 is a new E3 ligase for the tumor suppressor LATS1 and destabilizes LATS1 by promoting the ubiquitination of LATS1. miRNA-136-5p and miRNA-1285-5p, expression of which is decreased in human breast cancers and is inversely correlated with the prognosis of breast cancer patients, are directly involved in suppressing the expression of HERC4. In summary, we discover a miRNA-HERC4-LATS1 pathway that plays important roles in the pathogenesis of breast cancer and represents new therapeutic targets for human breast cancer.

Keywords

E3 ligase / tumorigenesis / ubiquitination / tumor suppressor / miRNA

References

[1] Bonanno L, Costa C, Majem M, Sanchez JJ, Rodriguez I, Gimenez-Capitan A, Molina-Vila MA, Vergnenegre A, Massuti B, Favaretto A (2016) Combinatory effect of BRCA1 and HERC2 expression on outcome in advanced non-small-cell lung cancer. BMC Cancer 16:312

[2] Britschgi A, Duss S, Kim S, Couto JP, Brinkhaus H, Koren S, De Silva D, Mertz KD, Kaup D, Varga Z (2017) The Hippo kinases LATS1 and 2 control human breast cell fate via crosstalk with ERalpha. Nature 541:541–545

[3] Campos-Parra AD, Mitznahuatl GC, Pedroza-Torres A, Romo RV, Reyes FIP, Lopez-Urrutia E, Perez-Plasencia C (2017) Micro-RNAs as potential predictors of response to breast cancer systemic therapy: future clinical implications. Int J Mol Sci 18(6): E1182

[4] Chan M, Liaw CS, Ji SM, Tan HH, Wong CY, Thike AA, Tan PH, Ho GH, Lee AS (2013) Identification of circulating microRNA signatures for breast cancer detection. Clin Cancer Res 19 (16):4477–4487

[5] Diouf B, Cheng Q,Krynetskaia NF, Yang W, Cheok M, Pei D, Fan Y, Cheng C, Krynetskiy EY, Geng H (2011) Somatic deletions of genes regulating MSH2 protein stability cause DNA mismatch repair deficiency and drug resistance in human leukemia cells. Nat Med 17:1298–1303

[6] Dubey AK, Gupta U, Jain S (2015) Breast cancer statistics and prediction methodology: a systematic review and analysis. Asian Pac J Cancer Prev 16:4237–4245

[7] Duffy MJ, Maguire TM, Hill A, McDermott E, O’Higgins N (2000) Metalloproteinases: role in breast carcinogenesis, invasion and metastasis. Breast Cancer Res 2:252–257

[8] Furth N, Aylon Y (2017) The LATS1 and LATS2 tumor suppressors: beyond the Hippo pathway. Cell Death Differ 24:1488–1501

[9] Hershko A (2005) The ubiquitin system for protein degradation and some of its roles in the control of the cell division cycle. Cell Death Differ 12:1191–1197

[10] Kim J, Liu Y, Qiu M, Xu Y (2015) Pluripotency factor Nanog is tumorigenic by deregulating DNA damage response in somatic cells. Oncogene 35:1334–1340

[11] Kim J, Xu S, Xiong L, Yu L, Fu X, Xu Y (2017) SALL4 promotes glycolysis and chromatin remodeling via modulating HP1α-Glut1 pathway. Oncogene 36:6472–6479

[12] Kulaberoglu Y, Lin K, Holder M, Gai Z, Gomez M, Assefa Shifa B, Mavis M, Hoa L, Sharif AAD, Lujan C (2017) Stable MOB1 interaction with Hippo/MST is not essential for development and tissue growth control. Nat Commun 8:695

[13] Lanczky A, Nagy A, Bottai G, Munkacsy G, Paladini L, Szabo A, Santarpia L, Gyorffy B (2016) miRpower: a web-tool to validate survival-associated miRNAs utilizing expression data from 2,178 breast cancer patients. Breast Cancer Res Treat 160(3):439–446

[14] Li DX, Fei XR, Dong YF, Cheng CD, Yang Y, Deng XF, Huang HL, Niu WX, Zhou CX, Xia CY (2017) The long non-coding RNA CRNDE acts as a ceRNA and promotes glioma malignancy by preventing miR-136-5p-mediated downregulation of Bcl-2 and Wnt2. Oncotarget 8:88163–88178

[15] Liu J, Yan J, Zhou C, Ma Q, Jin Q, Yang Z (2015) miR-1285-3p acts as a potential tumor suppressor miRNA via downregulating JUN expression in hepatocellular carcinoma. Tumour Biol 36:219–225

[16] Mayer IA, Dent R, Tan T, Savas P, Loi S (2017) Novel targeted agents and immunotherapy in breast cancer. Am Soc Clin Oncol Educ Book 37:65–75

[17] Micel LN, Tentler JJ, Smith PG, Eckhardt GS (2013) Role of ubiquitin ligases and the proteasome in oncogenesis: novel targets for anticancer therapies. J Clin Oncol 31:1231–1238

[18] Mitsui K, Nakanishi M, Ohtsuka S, Norwood TH, Okabayashi K, Miyamoto C, Tanaka K, Yoshimura A, Ohtsubo M (1999) A novel human gene encoding HECT domain and RCC1-like repeats interacts with cyclins and is potentially regulated by the tumor suppressor proteins. Biochem Biophys Res Commun 266:115–122

[19] Mofers A, Pellegrini P, Linder S, D’Arcy P (2017) Proteasomeassociated deubiquitinases and cancer. Cancer Metastasis Rev 36:635–653

[20] Patani N, Martin LA, Dowsett M (2013) Biomarkers for the clinical management of breast cancer: international perspective. Int J Cancer 133:1–13

[21] Pfleger CM (2017) The hippo pathway: a master regulatory network important in development and dysregulated in disease. Curr Top Dev Biol 123:181–228

[22] Rodriguez CI, Stewart CL (2007) Disruption of the ubiquitin ligase HERC4 causes defects in spermatozoon maturation and impaired fertility. Dev Biol 312:501–508

[23] Rong Z,Zhu S, Xu Y, Fu X (2014) Homologous recombination in human embryonic stem cells using CRISPR/Cas9 nickase and a long DNA donor template. Protein & Cell 5(4):1–3

[24] Rotin D, Kumar S (2009) Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol 10:398–409

[25] Rupaimoole R, Slack FJ (2017) MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov 16:203–222

[26] Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, Santos A, Doncheva NT, Roth A, Bork P, Jensen LJ, von Mering C. The STRING database in 2017: quality-controlled proteinprotein association networks, made broadly accessible. Nucleic Acids Res 2017; 45:D362–68

[27] Weidle UH, Dickopf S, Hintermair C, Kollmorgen G, Birzele F,Brinkmann U (2018) The role of micro RNAs in breast cancer metastasis: preclinical validation and potential therapeutic targets. Cancer Genom Proteom 15:17–39

[28] Yan M, Li X, Tong D, Han C, Zhao R, He Y, Jin X (2016) miR-136 suppresses tumor invasion and metastasis by targeting RASAL2 in triple-negative breast cancer. Oncol Rep 36:65–71

[29] Wang J, Zhang X, Beck AH, Collins LC, Chen WY, Tamimi RM, Hazra A, Brown M, Rosner B,Hankinson SE (2015) Alcohol consumption and risk of breast cancer by tumor receptor expression. Horm Cancer 6(5–6):237–46

[30] Zeng WL, Chen YW, Zhou H, Zhou JY, Wei M, Shi R (2015) Expression of HERC4 in lung cancer and its correlation with clinicopathological parameters. Asian Pac J Cancer Prev 16:513–517

[31] Zhang Z-N, Chung S-K, Xu Z, Xu Y (2014) Maintains the pluripotency of human embryonic stem cells by inactivating p53 through Sirt1-mediated deacetylation. Stem Cells 32:157–165

[32] Zheng Y, Li J, Pan C, Zhou G, Zhuge L, Jin L, Fang P (2017) HERC4 Is overexpressed in hepatocellular carcinoma and contributes to the proliferation and migration of hepatocellular carcinoma cells. DNA Cell Biol 36:490–500

[33] Zhou H, Shi R, Wei M, Zheng WL, Zhou JY, Ma WL (2013) The expression and clinical significance of HERC4 in breast cancer. Cancer Cell Int 13:113

RIGHTS & PERMISSIONS

The Author(s)