Nuclear Dbf2-related Kinase 1 functions as tumor suppressor in glioblastoma by phosphorylation of Yes-associated protein

Abstract

Background: The Nuclear Dbf2-related (NDR1) kinase is a member of the NDR/LATS family, which was a supplementary of Hippo pathway. However, whether NDR1 could inhibit glioblastoma (GBM) growth by phosphorylating Yes-associated protein (YAP) remains unknown. Meanwhile, the role of NDR1 in GBM was not clear. This study aimed to investigate the role of NDR1-YAP pathway in GBM. Methods: Bioinformation analysis and immunohistochemistry (IHC) were performed to identify the expression of NDR1 in GBM. The effect of NDR1 on cell proliferation and cell cycle was analyzed utilizing CCK-8, clone formation, immunofluorescence and flow cytometry, respectively. In addition, the xenograft tumor model was established as well. Protein interaction was examined by Co-immunoprecipitation and immunofluorescence to observe co-localization. Results: Bioinformation analysis and IHC of our patients’ tumor tissues showed that expression of NDR1 in tumor tissue was relatively lower than that in normal tissues and was positively related to a lower survival rate. NDR1 could markedly reduce the proliferation and colony formation of U87 and U251. Furthermore, the results of flow cytometry showed that NDR1 led to cell cycle arrest at the G1 phase. Tumor growth was also inhibited in xenograft nude mouse models in NDR1-overexpression group. Western blotting and immunofluorescence showed that NDR1 could integrate with and phosphorylate YAP at S127 site. Meanwhile, NDR1 could mediate apoptosis process. Conclusion: In summary, our findings point out that NDR1 functions as a tumor suppressor in GBM. NDR1 is identified as a novel regulator of YAP, which gives us an in-depth comprehension of the Hippo signaling pathway.

The mechanism of BUD13 m6A methylation mediated MBNL1-phosphorylation by CDK12 regulating the vasculogenic mimicry in glioblastoma cells

“…Ser-436 phosphorylation promoted YAP-mediated GBM proliferation, migration, and invasion [ 60 ]. NDR1 inhibited GBM progression by phosphorylating YAP [ 61 ]. PIKE-A regulated STAT3 phosphorylation-mediated G6PD expression to promote GBM cell proliferation and anti-ROS stress response [ 62 ].…”

The Role of Mammalian STK38 in DNA Damage Response and Targeting for Radio-Sensitization

“…Recently, a pan-cancer analysis of STK38 reveals that the expression of STK38 is associated with patient survival, immune cell infiltration such as NK cells, cancer-associated fibroblasts, tumor mutation burden and microsatellite instability in several human cancers [ 66 ]. However, there is also evidence that STK38 can reduce the cell proliferation of glioblastomas and inhibit the metastasis of prostate cancer [ 67 ]. STK38/STK38L kinases phosphorylate the transcriptional coactivator yes-associated protein (YAP1) and thereby negatively regulate YAP1 transcriptional activity, suggesting that STK38/STK38L function as tumor suppressors [ 68 ].…”

The Role of Protein SUMOylation in Human Hepatocellular Carcinoma: A Potential Target of New Drug Discovery and Development

“…Large tumour suppressor genes (Lats) can enhance the homeostasis of cells. Furthermore, it can mediate Hippo’s inhibitory signal [ 82 ]. Liu and Mei et al found that SUMO of Lats1 affects its kinase activity, especially Hippo signal transduction [ 64 ].…”