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MPDZ as a novel epigenetic silenced tumor suppressor inhibits growth and progression of lung cancer through the Hippo-YAP pathway

Abstract

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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Fig. 1: MPDZ promoter CpG island region frequently hypermethylated in lung cancer tissues, plasma and sputum samples, and cell lines.
Fig. 2: MPDZ downexpressed associated with DNA methylation and had poor prognosis in lung cancer patients.
Fig. 3: MPDZ overexpression inhibits cell proliferation, migration, and invasion.
Fig. 4: MPDZ knockdown promotes cell proliferation, migration, and invasion in vitro.
Fig. 5: Knockdown of MPDZ promotes tumor progression in nude mice.
Fig. 6: MPDZ deficiency promotes tumor metastasis in knockout mouse.
Fig. 7: MPDZ regulated Hippo pathway by inhibiting YAP.
Fig. 8: MPDZ inhibited YAP through stabilizing MST1 and interaction with LATS1.
Fig. 9: Schematic diagram of epigenetic regulation, function, and molecular mechanism of MPDZ in lung cancer.

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Acknowledgements

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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WL and YH conceived the study, carried out experiments, analyzed data, and drafted the manuscript. DW, FH, HC, JChen, and XJ carried out experiments. WL, JCao, and JL conceived and supervised the study, analyzed data, and finalized the manuscript. All authors were involved in writing the paper and had final approval of the submitted and published versions.

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Correspondence to Wenbin Liu or Jia Cao or Jinyi Liu.

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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

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