MPDZ also named MUPP1 is involved in signal transduction mediated by the formation of protein complexes. However, the expression regulation, clinical significance, potential function, and mechanism of this gene in lung cancer remain unclear. Methylation status of MPDZ was measured by methylation-specific PCR and bisulfite genomic sequencing. Kaplan–Meier and Cox regression analyses were performed to identify the prognostic value of MPDZ. The tumor suppressing effects of MPDZ were determined in vitro and in vivo. The target molecules and signaling pathway that mediated the function of MPDZ were also identified. MPDZ methylation was identified in 61.2% of primary lung cancer tissues and most lung cancer cell lines but not in normal lung tissues. MPDZ expression was significantly downregulated in lung cancer tissues and negatively associated with DNA hypermethylation, and attenuated MPDZ expression predicted a poor outcome. Furthermore, MPDZ overexpression prominently dampened cell growth, migration, and invasion of tumor cells. Conversely, MPDZ knockdown promoted cell proliferation, migration, and invasion in vitro and in vivo. Moreover, MPDZ deficiency promotes tumor metastasis and reduces the survival of MPDZ knockout mice. Importantly, MPDZ promotes tumor suppressor ability that depends on the Hippo pathway-mediated repression of YAP. MPDZ activates the phosphorylation of YAP (Ser127) and inhibits YAP expression through stabilizing MST1 and interaction with LATS1. We first identified and validated that MPDZ methylation and expression could be a good diagnostic marker and independent prognostic factor for lung cancer. MPDZ functions as a tumor suppressor by inhibiting cell proliferation, migration, and invasion through regulating the Hippo-YAP signaling pathway.
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Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. Cancer J Clin. 2016;66:7–30.
Berger AH, Brooks AN, Wu X, Shrestha Y, Chouinard C, Piccioni F, et al. High-throughput phenotyping of lung cancer somatic mutations. Cancer Cell. 2016;30:214–28.
Belinsky SA. Unmasking the lung cancer epigenome. Annu Rev Physiol. 2015;77:453–74.
Rodríguez-Paredes M, Esteller M. Cancer epigenetics reaches mainstream oncology. Nat Med. 2011;17:330–9.
Li E, Zhang Y. DNA methylation in mammals. CSH Perspect Biol. 2014;6:a19133.
Feil R, Fraga MF. Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet. 2012;13:97–109.
De Carvalho DD, Sharma S, You JS, Su SF, Taberlay PC, Kelly TK, et al. DNA methylation screening identifies driver epigenetic events of cancer cell survival. Cancer Cell. 2012;21:655–67.
Zhu H, Wu K, Yan W, Hu L, Yuan J, Dong Y, et al. Epigenetic silencing of DACH1 induces loss of transforming growth factor-β1 antiproliferative response in human hepatocellular carcinoma. Hepatology. 2013;58:2012–22.
Liu WB, Han F, Jiang X, Chen HQ, Zhao H, Liu Y, et al. TMEM196 acts as a novel functional tumour suppressor inactivated by DNA methylation and is a potential prognostic biomarker in lung cancer. Oncotarget. 2015;6:21225–39.
Han F, Liu W, Jiang X, Shi X, Yin L, Ao L, et al. SOX30, a novel epigenetic silenced tumor suppressor, promotes tumor cell apoptosis by transcriptional activating p53 in lung cancer. Oncogene. 2015;34:4391–402.
Yuan S, Yu Z, Liu Q, Zhang M, Xiang Y, Wu N, et al. GPC5, a novel epigenetically silenced tumor suppressor, inhibits tumor growth by suppressing Wnt/beta-catenin signaling in lung adenocarcinoma. Oncogene. 2016;35:6120–31.
Liu WB, Jiang X, Han F, Li YH, Chen HQ, Liu Y, et al. LHX6 acts as a novel potential tumour suppressor with epigenetic inactivation in lung cancer. Cell Death Dis. 2013;4:e882.
Liu WB, Han F, Du XH, Jiang X, Li YH, Liu Y, et al. Epigenetic silencing of Aristaless-like homeobox-4, a potential tumor suppressor gene associated with lung cancer. Int J Cancer. 2014;134:1311–22.
Ullmer C, Schmuck K, Figge A, Lubbert H. Cloning and characterization of MUPP1, a novel PDZ domain protein. FEBS Lett. 1998;424:63–8.
Guillaume JL, Daulat AM, Maurice P, Levoye A, Migaud M, Brydon L, et al. The PDZ protein Mupp1 promotes Gi coupling and signaling of the Mt1 melatonin receptor. J Biol Chem. 2008;283:16762–71.
Krapivinsky G, Medina I, Krapivinsky L, Gapon S, Clapham DE. SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent synaptic AMPA receptor potentiation. Neuron. 2004;43:563–74.
Lanaspa MA, Almeida NE, Andres-Hernando A, Rivard CJ, Capasso JM, Berl T. The tight junction protein, MUPP1, is up-regulated by hypertonicity and is important in the osmotic stress response in kidney cells. Proc Natl Acad Sci USA. 2007;104:13672–7.
Lanaspa MA, Andres-Hernando A, Rivard CJ, Dai Y, Berl T. Hypertonic stress increases claudin-4 expression and tight junction integrity in association with MUPP1 in IMCD3 cells. Proc Natl Acad Sci USA. 2008;105:15797–802.
Coyne CB, Voelker T, Pichla SL, Bergelson JM. The coxsackievirus and adenovirus receptor interacts with the multi-PDZ domain protein-1 (MUPP-1) within the tight junction. J Biol Chem. 2004;279:48079–84.
Martin TA, Watkins G, Mansel RE, Jiang WG. Loss of tight junction plaque molecules in breast cancer tissues is associated with a poor prognosis in patients with breast cancer. Eur J Cancer. 2004;40:2717–25.
Massimi P, Gammoh N, Thomas M, Banks L. HPV E6 specifically targets different cellular pools of its PDZ domain-containing tumour suppressor substrates for proteasome-mediated degradation. Oncogene. 2004;23:8033–9.
Sheu JJC, Lee CH, Ko JY, Tsao GSW, Wu CC, Fang CY, et al. Chromosome 3p12.3-p14.2 and 3q26.2-q26.32 are genomic markers for prognosis of advanced nasopharyngeal carcinoma. Cancer Epidemiol Biomar. 2009;18:2709–16.
Ishiuchi T, Misaki K, Yonemura S, Takeichi M, Tanoue T. Mammalian fat and dachsous cadherins regulate apical membrane organization in the embryonic cerebral cortex. J Cell Biol. 2009;185:959–67.
Lee YS, Lee JW, Jang JW, Chi XZ, Kim JH, Li YH, et al. Runx3 inactivation is a crucial early event in the development of lung adenocarcinoma. Cancer Cell. 2013;24:603–16.
Mohammad HP, Smitheman KN, Kamat CD, Soong D, Federowicz KE, Van Aller GS, et al. A DNA hypomethylation signature predicts antitumor activity of LSD1 inhibitors in SCLC. Cancer Cell. 2015;28:57–69.
Liu W, Han F, Jiang X, Yin L, Chen H, Li Y, et al. Epigenetic regulation of ANKRD18B in lung cancer. Mol Carcinog. 2015;54:312–21.
Liu Y, An Q, Li L, Zhang D, Huang J, Feng X, et al. Hypermethylation of p16INK4a in Chinese lung cancer patients: biological and clinical implications. Carcinogenesis. 2003;24:1897–901.
Nawaz I, Qiu X, Wu H, Li Y, Fan Y, Hu L, et al. Development of a multiplex methylation specific PCR suitable for (early) detection of non-small cell lung cancer. Epigenetics. 2014;9:1138–48.
Hubers AJ, Heideman DAM, Burgers SA, Herder GJM, Sterk PJ, Rhodius RJ, et al. DNA hypermethylation analysis in sputum for the diagnosis of lung cancer: training validation set approach. Brit J Cancer. 2015;112:1105–13.
Wrangle J, Machida EO, Danilova L, Hulbert A, Franco N, Zhang W, et al. Functional identification of cancer-specific methylation of CDO1, HOXA9, and TAC1 for the diagnosis of lung cancer. Clin Cancer Res. 2014;20:1856–64.
Yang J, Simonneau C, Kilker R, Oakley L, Byrne MD, Nichtova Z, et al. Murine MPDZ-linked hydrocephalus is caused by hyperpermeability of the choroid plexus. EMBO Mol Med. 2019;11:e9540.
Feldner A, Adam MG, Tetzlaff F, Moll I, Komljenovic D, Sahm F, et al. Loss of Mpdz impairs ependymal cell integrity leading to perinatal-onset hydrocephalus in mice. EMBO Mol Med. 2017;9:890–905.
Tetzlaff F, Adam MG, Feldner A, Moll I, Menuchin A, Rodriguez-Vita J, et al. MPDZ promotes DLL4-induced Notch signaling during angiogenesis. Elife. 2018;7:e32860.
Johnson R, Halder G. The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment. Nat Rev Drug Discov. 2014;13:63–79.
Piccolo S, Dupont S, Cordenonsi M. The biology of YAP/TAZ: Hippo signaling and beyond. Physiol Rev. 2014;94:1287–312.
Yu FX, Zhao B, Guan KL. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell. 2015;163:811–28.
Zanconato F, Cordenonsi M, Piccolo S. YAP/TAZ at the roots of cancer. Cancer Cell. 2016;29:783–803.
Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nat Rev Cancer. 2013;13:246–57.
Zhao B, Li L, Wang L, Wang CY, Yu J, Guan KL. Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev. 2012;26:54–68.
Walko G, Woodhouse S, Pisco AO, Rognoni E, Liakath-Ali K, Lichtenberger BM, et al. A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells. Nat Commun. 2017;8:14744.
Zhang X, George J, Deb S, Degoutin JL, Takano EA, Fox SB, et al. The Hippo pathway transcriptional co-activator, YAP, is an ovarian cancer oncogene. Oncogene. 2011;30:2810–22.
Hsu YL, Hung JY, Chou SH, Huang MS, Tsai MJ, Lin YS, et al. Angiomotin decreases lung cancer progression by sequestering oncogenic YAP/TAZ and decreasing Cyr61 expression. Oncogene. 2015;34:4056–68.
Zhao B, Li L, Lu Q, Wang LH, Liu CY, Lei Q, et al. Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein. Genes Dev. 2011;25:51–63.
Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 2007;21:2747–61.
Hao Y, Chun A, Cheung K, Rashidi B, Yang X. Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J Biol Chem. 2008;283:5496–509.
Liu J, Ye L, Li Q, Wu X, Wang B, Ouyang Y, et al. Synaptopodin-2 suppresses metastasis of triple-negative breast cancer via inhibition of YAP/TAZ activity. J Pathol 2018;244:71–83.
Wang J, Sinnett-Smith J, Stevens JV, Young SH, Rozengurt E. Biphasic regulation of yes-associated protein (YAP) cellular localization, phosphorylation, and activity by G protein-coupled receptor agonists in intestinal epithelial cells: a novel role for protein kinase D (PKD). J Biol Chem. 2016;291:17988–8005.
Wen X, Wan J, He Q, Wang M, Li S, Jiang M, et al. p190A inactivating mutations cause aberrant RhoA activation and promote malignant transformation via the Hippo-YAP pathway in endometrial cancer. Signal Transduct Target Ther. 2020;5:81.
Zhang YL, Li Q, Yang XM, Fang F, Li J, Wang YH, et al. SPON2 promotes M1-like macrophage recruitment and inhibits hepatocellular carcinoma metastasis by distinct integrin-rho GTPase-Hippo pathways. Cancer Res. 2018;78:2305–17.
This work was supported by grants from the National Natural Science Foundation of China (No. 81573179) and the Natural Science Foundation Project of Chongqing CSTC of China (No. cstc2018jcyjAX0233). The authors sincerely thank Yajing Li for technical help.
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Liu, W., Huang, Y., Wang, D. et al. MPDZ as a novel epigenetic silenced tumor suppressor inhibits growth and progression of lung cancer through the Hippo-YAP pathway. Oncogene (2021). https://doi.org/10.1038/s41388-021-01857-8