Abstract
PINCH-1 is a cytoplasmic component of the cell-extracellular matrix (ECM) adhesion machine that is frequently overexpressed in cancer. The functions and mechanism of PINCH-1 in cancer, however, remain to be determined. Here, we show that PINCH-1 interacts with myoferlin, a transmembrane protein that is critical for cancer progression. High expression of both PINCH-1 and myoferlin correlates with poor clinical outcome in human breast cancer patients. Ablation of PINCH-1 from breast cancer cells diminished myoferlin level and suppressed breast cancer cell proliferation, migration, and endothelial cell tube formation in vitro and breast tumor growth, angiogenesis and metastasis in vivo. Mechanistically, PINCH-1 controls myoferlin level through its interaction with myoferlin and regulation of its ubiquitination and proteasome-dependent degradation. Functionally, re-expression of PINCH-1, but not that of a myoferlin-binding defectiveΔLIM2 mutant, effectively reversed the inhibition of myoferlin expression and breast cancer progression induced by loss of PINCH-1. Finally, restoration of myoferlin expression was sufficient to reverse PINCH-1-deficiency induced inhibition on breast cancer progression. These results reveal a PINCH-1-myoferlin signaling axis that is critical for breast cancer progression and suggest a new strategy for therapeutic control of breast cancer.
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References
Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. J Cell Sci. 2012;125:5591–6.
Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423–37.
Seager RJ, Hajal C, Spill F, Kamm RD, Zaman MH. Dynamic interplay between tumour, stroma and immune system can drive or prevent tumour progression. Convergent Sci Phys Oncol. 2017;3:034002.
Ungefroren H, Sebens S, Seidl D, Lehnert H, Hass R. Interaction of tumor cells with the microenvironment. Cell Commun Signal. 2011;9:18.
Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2010;10:9–22.
Gkretsi V, Stylianopoulos T. Cell adhesion and matrix stiffness: coordinating cancer cell invasion and metastasis. Front Oncol. 2018;8:145.
Longmate W, DiPersio CM. Beyond adhesion: emerging roles for integrins in control of the tumor microenvironment. F1000Res. 2017;6:1612.
Seguin L, Desgrosellier JS, Weis SM, Cheresh DA. Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol. 2015;25:234–40.
Goodman SL, Picard M. Integrins as therapeutic targets. Trends Pharm Sci. 2012;33:405–12.
Hamidi H, Pietila M, Ivaska J. The complexity of integrins in cancer and new scopes for therapeutic targeting. Br J Cancer. 2016;115:1017–23.
Hannigan G, Troussard AA, Dedhar S. Integrin-linked kinase: a cancer therapeutic target unique among its ILK. Nat Rev Cancer. 2005;5:51–63.
Harisi R, Jeney A. Extracellular matrix as target for antitumor therapy. Onco Targets Ther. 2015;8:1387–98.
Zheng CC, Hu HF, Hong P, Zhang QH, Xu WW, He QY, et al. Significance of integrin-linked kinase (ILK) in tumorigenesis and its potential implication as a biomarker and therapeutic target for human cancer. Am J Cancer Res. 2019;9:186–97.
Humphries JD, Chastney MR, Askari JA, Humphries MJ. Signal transduction via integrin adhesion complexes. Curr Opin Cell Biol. 2019;56:14–21.
Whittaker CA, Bergeron KF, Whittle J, Brandhorst BP, Burke RD, Hynes RO. The echinoderm adhesome. Dev Biol. 2006;300:252–66.
Winograd-Katz SE, Fassler R, Geiger B, Legate KR. The integrin adhesome: from genes and proteins to human disease. Nat Rev Mol Cell Biol. 2014;15:273–88.
Zaidel-Bar R, Itzkovitz S, Ma'ayan A, Iyengar R, Geiger B. Functional atlas of the integrin adhesome. Nat Cell Biol. 2007;9:858–67.
Chen K, Tu Y, Zhang Y, Blair HC, Zhang L, Wu C. PINCH-1 regulates the ERK-Bim pathway and contributes to apoptosis resistance in cancer cells. J Biol Chem. 2008;283:2508–17.
Fukuda T, Chen K, Shi X, Wu C. PINCH-1 is an obligate partner of integrin-linked kinase (ILK) functioning in cell shape modulation, motility, and survival. J Biol Chem. 2003;278:51324–33.
Legate KR, Montanez E, Kudlacek O, Fassler R. ILK, PINCH and parvin: the tIPP of integrin signalling. Nat Rev Mol Cell Biol. 2006;7:20–31.
Li S, Bordoy R, Stanchi F, Moser M, Braun A, Kudlacek O, et al. PINCH1 regulates cell-matrix and cell-cell adhesions, cell polarity and cell survival during the peri-implantation stage. J Cell Sci. 2005;118:2913–21.
Tu Y, Li F, Goicoechea S, Wu C. The LIM-only protein PINCH directly interacts with integrin-linked kinase and is recruited to integrin-rich sites in spreading cells. Mol Cell Biol. 1999;19:2425–34.
Wu C. The PINCH-ILK-parvin complexes: assembly, functions and regulation. Biochim Biophys Acta. 2004;1692:55–62.
Qin J, Wu C. ILK: a pseudokinase in the center stage of cell-matrix adhesion and signaling. Curr Opin Cell Biol. 2012;24:607–13.
Tu Y, Huang Y, Zhang Y, Hua Y, Wu C. A new focal adhesion protein that interacts with integrin-linked kinase and regulates cell adhesion and spreading. J Cell Biol. 2001;153:585–98.
Wickstrom SA, Lange A, Montanez E, Fassler R. The ILK/PINCH/parvin complex: the kinase is dead, long live the pseudokinase! EMBO J. 2010;29:281–91.
Wu C. PINCH, N(i)ck and the ILK: network wiring at cell-matrix adhesions. Trends Cell Biol. 2005;15:460–6.
Zhang Y, Chen K, Tu Y, Velyvis A, Yang Y, Qin J, et al. Assembly of the PINCH-ILK-CH-ILKBP complex precedes and is essential for localization of each component to cell-matrix adhesion sites. J Cell Sci. 2002;115:4777–86.
Kovalevich J, Tracy B, Langford D. PINCH: More than just an adaptor protein in cellular response. J Cell Physiol. 2011;226:940–7.
Liang X, Zhou Q, Li X, Sun Y, Lu M, Dalton N, et al. PINCH1 plays an essential role in early murine embryonic development but is dispensable in ventricular cardiomyocytes. Mol Cell Biol. 2005;25:3056–62.
Vakaloglou KM, Chrysanthis G, Rapsomaniki MA, Lygerou Z, Zervas CG. IPP complex reinforces adhesion by relaying tension-dependent signals to inhibit integrin turnover. Cell Rep. 2016;16:596.
Zhang Y, Chen K, Guo L, Wu C. Characterization of PINCH-2, a new focal adhesion protein that regulates the PINCH-1-ILK interaction, cell spreading, and migration. J Biol Chem. 2002;277:38328–38.
Wang-Rodriguez J, Dreilinger AD, Alsharabi GM, Rearden A. The signaling adapter protein PINCH is up-regulated in the stroma of common cancers, notably at invasive edges. Cancer. 2002;95:1387–95.
Eke I, Koch U, Hehlgans S, Sandfort V, Stanchi F, Zips D, et al. PINCH1 regulates Akt1 activation and enhances radioresistance by inhibiting PP1alpha. J Clin Invest. 2010;120:2516–27.
Loof J, Rosell J, Bratthall C, Dore S, Starkhammar H, Zhang H, et al. Impact of PINCH expression on survival in colorectal cancer patients. BMC Cancer. 2011;11:103.
Zhu Z, Yang Y, Zhang Y, Wang Z, Cui D, Zhang J, et al. PINCH expression and its significance in esophageal squamous cell carcinoma. Dis Markers. 2008;25:75–80.
Wang MW, Gu P, Zhang ZY, Zhu ZL, Li YM, Zhao HX, et al. Expression of PINCH protein in gliomas and its clinicopathological significance. Oncology. 2007;72:343–6.
Bernatchez PN, Sharma A, Kodaman P, Sessa WC. Myoferlin is critical for endocytosis in endothelial cells. Am J Physiol Cell Physiol. 2009;297:C484–92.
Cipta S, Patel HH. Molecular bandages: inside-out, outside-in repair of cellular membranes. Focus on “Myoferlin is critical for endocytosis in endothelial cells”. Am J Physiol Cell Physiol. 2009;297:C481–3.
Davis DB, Delmonte AJ, Ly CT, McNally EM. Myoferlin, a candidate gene and potential modifier of muscular dystrophy. Hum Mol Genet. 2000;9:217–26.
Doherty KR, Demonbreun AR, Wallace GQ, Cave A, Posey AD, Heretis K, et al. The endocytic recycling protein EHD2 interacts with myoferlin to regulate myoblast fusion. J Biol Chem. 2008;283:20252–60.
Rademaker G, Hennequiere V, Brohee L, Nokin MJ, Lovinfosse P, Durieux F, et al. Myoferlin controls mitochondrial structure and activity in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness. Oncogene. 2018;37:4398–412.
Blomme A, Costanza B, de Tullio P, Thiry M, Van Simaeys G, Boutry S, et al. Myoferlin regulates cellular lipid metabolism and promotes metastases in triple-negative breast cancer. Oncogene. 2017;36:2116–30.
Turtoi A, Blomme A, Bellahcene A, Gilles C, Hennequiere V, Peixoto P, et al. Myoferlin is a key regulator of EGFR activity in breast cancer. Cancer Res. 2013;73:5438–48.
Fahmy K, Gonzalez A, Arafa M, Peixoto P, Bellahcene A, Turtoi A, et al. Myoferlin plays a key role in VEGFA secretion and impacts tumor-associated angiogenesis in human pancreas cancer. Int J Cancer. 2016;138:652–63.
Hermanns C, Hampl V, Holzer K, Aigner A, Penkava J, Frank N, et al. The novel MKL target gene myoferlin modulates expansion and senescence of hepatocellular carcinoma. Oncogene. 2017;36:3464–76.
Kim MH, Song DH, Ko GH, Lee JH, Kim DC, Yang JW, et al. Myoferlin expression and its correlation with FIGO histologic grading in early-stage endometrioid carcinoma. J Pathol Transl Med. 2018;52:93–7.
Kumar B, Brown NV, Swanson BJ, Schmitt AC, Old M, Ozer E, et al. High expression of myoferlin is associated with poor outcome in oropharyngeal squamous cell carcinoma patients and is inversely associated with HPV-status. Oncotarget. 2016;7:18665–77.
Song DH, Ko GH, Lee JH, Lee JS, Lee GW, Kim HC, et al. Myoferlin expression in non-small cell lung cancer: Prognostic role and correlation with VEGFR-2 expression. Oncol Lett. 2016;11:998–1006.
Blackstone BN, Li R, Ackerman WEt, Ghadiali SN, Powell HM, Kniss DA. Myoferlin depletion elevates focal adhesion kinase and paxillin phosphorylation and enhances cell-matrix adhesion in breast cancer cells. Am J Physiol Cell Physiol. 2015;308:C642–9.
Leung C, Yu C, Lin MI, Tognon C, Bernatchez P. Expression of myoferlin in human and murine carcinoma tumors: role in membrane repair, cell proliferation, and tumorigenesis. Am J Pathol. 2013;182:1900–9.
Li R, Ackerman WEt, Mihai C, Volakis LI, Ghadiali S, Kniss DA. Myoferlin depletion in breast cancer cells promotes mesenchymal to epithelial shape change and stalls invasion. PLoS ONE. 2012;7:e39766.
Zhang T, Li J, He Y, Yang F, Hao Y, Jin W, et al. A small molecule targeting myoferlin exerts promising anti-tumor effects on breast cancer. Nat Commun. 2018;9:3726.
Bernatchez PN, Acevedo L, Fernandez-Hernando C, Murata T, Chalouni C, Kim J, et al. Myoferlin regulates vascular endothelial growth factor receptor-2 stability and function. J Biol Chem. 2007;282:30745–53.
Yu C, Sharma A, Trane A, Utokaparch S, Leung C, Bernatchez P. Myoferlin gene silencing decreases Tie-2 expression in vitro and angiogenesis in vivo. Vasc Pharm. 2011;55:26–33.
Dong Y, Van Tine BA, Oyama T, Wang PI, Cheng EH, Hsieh JJ. Taspase1 cleaves MLL1 to activate cyclin E for HER2/neu breast tumorigenesis. Cell Res. 2014;24:1354–66.
Sun Y, Guo C, Ma P, Lai Y, Yang F, Cai J, et al. Kindlin-2 association with Rho GDP-dissociation inhibitor alpha suppresses Rac1 activation and podocyte injury. J Am Soc Nephrol. 2017;28:3545–62.
Sun Y, Duan Y, Eisenstein AS, Hu W, Quintana A, Lam WK, et al. A novel mechanism of control of NFkappaB activation and inflammation involving A2B adenosine receptors. J Cell Sci. 2012;125:4507–17.
Chen W, Wang S, Adhikari S, Deng Z, Wang L, Chen L, et al. Simple and integrated spintip-based technology applied for deep proteome profiling. Anal Chem. 2016;88:4864–71.
Moon S, Han D, Kim Y, Jin J, Ho WK, Kim Y. Interactome analysis of AMP-activated protein kinase (AMPK)-alpha1 and -beta1 in INS-1 pancreatic beta-cells by affinity purification-mass spectrometry. Sci Rep. 2014;4:4376.
Sun Y, Ding Y, Guo C, Liu C, Ma P, Ma S, et al. Alpha-Parvin promotes breast cancer progression and metastasis through interaction with G3BP2 and regulation of TWIST1 signaling. Oncogene. 2019;38:4856–74.
Hu W, Yu X, Liu Z, Sun Y, Chen X, Yang X, et al. The complex of TRIP-Br1 and XIAP ubiquitinates and degrades multiple adenylyl cyclase isoforms. Elife. 2017;6:e28021.
Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1809 patients. Breast Cancer Res Treat. 2010;123:725–31.
Barnhouse VR, Weist JL, Shukla VC, Ghadiali SN, Kniss DA, Leight JL. Myoferlin regulates epithelial cancer cell plasticity and migration through autocrine TGF-beta1 signaling. Oncotarget. 2018;9:19209–22.
Volakis LI, Li R, Ackerman WEt, Mihai C, Bechel M, Summerfield TL, et al. Loss of myoferlin redirects breast cancer cell motility towards collective migration. PLoS ONE. 2014;9:e86110.
Guy CT, Cardiff RD, Muller WJ. Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol. 1992;12:954–61.
Lin EY, Jones JG, Li P, Zhu L, Whitney KD, Muller WJ, et al. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol. 2003;163:2113–26.
Acknowledgements
We thank Dr. Ruijun Tian of the Department of Chemistry, Southern University of Science and Technology, for help with nano-LC-MS/MS analysis; Dr. Jiahuai Han (Xiamen University, China) for the myoferlin cDNA; Drs. Jason D. Weber (Washington University) and Yandong Zhang (Southern University of Science and Technology) for the 3× Flag tagged pLVX-IRES-Hyg vector; Dr. Andrew Hutchins (Southern University of Science and Technology) for comments on the manuscript. This work was supported by the National Natural Science Foundation of China (81772983, 81430068, and 31471311), the Chinese Ministry of Science and Technology (2016YFC1302100), the Natural Science Foundation of Guangdong Province (1914050005629 and 2017B030301018), the Shenzhen Innovation Committee of Science and Technology, China (JCYJ20170817104854302, ZDSYS20140509142721429, and JCYJ20150831142427959).
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YS and CW designed the study, supervised the project and wrote the manuscript; TQ, CL, YD, CG, RC, XW, RW, KZ, and LZ performed the experiments and data analysis; YD advised on some of experiments.
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Qian, T., Liu, C., Ding, Y. et al. PINCH-1 interacts with myoferlin to promote breast cancer progression and metastasis. Oncogene 39, 2069–2087 (2020). https://doi.org/10.1038/s41388-019-1135-5
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DOI: https://doi.org/10.1038/s41388-019-1135-5
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