O-GlcNAcylation promotes migration and invasion in human ovarian cancer cells via the RhoA/ROCK/MLC pathway

Niu, Yichao; Xia, Ye; Wang, Jingyun; Shi, Xiaofei

doi:10.3892/mmr.2017.6244

Cited by 26 publications

(15 citation statements)

References 48 publications

(47 reference statements)

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“…Lastly, in SKOV3 and 59M ovarian cells, siRNA targeting OGT suppressed the cellular migration and invasion, whereas Thiamet-G (OGA inhibitor) bolstered it. More importantly, Thiamet-G boosted RhoA activity and the phosphorylation of Rho kinase substrates, whereas siOGT dampened RhoA activity and subsequent Rho kinase substrate phosphorylation (24). Collectively, O-GlcNAcylation may fuel the RhoA/Rho kinase signaling pathway.…”

Section: Chk1 Phosphorylates Ogt In Cytokinesismentioning

confidence: 94%

Checkpoint kinase 1–induced phosphorylation of O-linked β-N-acetylglucosamine transferase regulates the intermediate filament network during cytokinesis

Nai

et al. 2017

Journal of Biological Chemistry

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Checkpoint kinase 1 (Chk1) is a kinase instrumental for orchestrating DNA replication, DNA damage checkpoints, the spindle assembly checkpoint, and cytokinesis. Despite Chk1's pivotal role in multiple cellular processes, many of its substrates remain elusive. Here, we identified linked β--acetylglucosamine (-GlcNAc)-transferase (OGT) as one of Chk1's substrates. We found that Chk1 interacts with and phosphorylates OGT at Ser-20, which not only stabilizes OGT, but also is required for cytokinesis. Phospho-specific antibodies of OGT-pSer-20 exhibited specific signals at the midbody of the cell, consistent with midbody localization of OGT as reported previously. Moreover, phospho-deficient OGT (S20A) cells attenuated cellular -GlcNAcylation levels and also reduced phosphorylation of Ser-71 in the cytoskeletal protein vimentin, a modification critical for severing vimentin filament during cytokinesis. Consequently, elongated vimentin bridges were observed in cells depleted of OGT via an sibased approach. Lastly, expression of plasmids resistant to si efficiently rescued the vimentin bridge phenotype, but the OGT-S20A rescue plasmids did not. Our results suggest a Chk1-OGT-vimentin pathway that regulates the intermediate filament network during cytokinesis.

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Section: Chk1 Phosphorylates Ogt In Cytokinesismentioning

confidence: 94%

Checkpoint kinase 1–induced phosphorylation of O-linked β-N-acetylglucosamine transferase regulates the intermediate filament network during cytokinesis

Nai

et al. 2017

Journal of Biological Chemistry

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“…This allow Rho family GTPases to regulate cytoskeleton-mediated cell shape, motility and division 4 . Rho family members also control multiple intracellular signaling pathways 5 – 9 , including signaling initiated by the mammalian target of rapamycin complex-1 (mTORC1) 5 , 6 , 10 .…”

Section: Introductionmentioning

confidence: 99%

Simulated microgravity inhibits cell focal adhesions leading to reduced melanoma cell proliferation and metastasis via FAK/RhoA-regulated mTORC1 and AMPK pathways

Tan

Zhao

et al. 2018

Sci Rep

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Simulated microgravity (SMG) was reported to affect tumor cell proliferation and metastasis. However, the underlying mechanism is elusive. In this study, we demonstrate that clinostat-modelled SMG reduces BL6-10 melanoma cell proliferation, adhesion and invasiveness in vitro and decreases tumor lung metastasis in vivo. It down-regulates metastasis-related integrin α6β4, MMP9 and Met72 molecules. SMG significantly reduces formation of focal adhesions and activation of focal adhesion kinase (FAK) and Rho family proteins (RhoA, Rac1 and Cdc42) and of mTORC1 kinase, but activates AMPK and ULK1 kinases. We demonstrate that SMG inhibits NADH induction and glycolysis, but induces mitochondrial biogenesis. Interestingly, administration of a RhoA activator, the cytotoxic necrotizing factor-1 (CNF1) effectively converts SMG-triggered alterations and effects on mitochondria biogenesis or glycolysis. CNF1 also converts the SMG-altered cell proliferation and tumor metastasis. In contrast, mTORC inhibitor, rapamycin, produces opposite responses and mimics SMG-induced effects in cells at normal gravity. Taken together, our observations indicate that SMG inhibits focal adhesions, leading to inhibition of signaling FAK and RhoA, and the mTORC1 pathway, which results in activation of the AMPK pathway and reduced melanoma cell proliferation and metastasis. Overall, our findings shed a new light on effects of microgravity on cell biology and human health.

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“…Increased O-GlcNAcylation, OGT and UDP-GlcNAc levels are also detected in lymphocytes of chronic lymphocytic leukemia patients [43]; unlike what we have obtained in above-mentioned tumor types, higher O-GlcNAc levels in chronic lymphocytic leukemia patients depress CD38 expression, prolong ymphocyte doubling times and indicate a relatively good prognosis [43]. Distinguishingly, O-GlcNAcylation is decreased in ovarian tumors compared with normal tissue [104]; however, O-GlcNAcylation augments the migration and invasion of SKOV3 and 59M [48,104,105] ↓/↓ migration↑, invasion↑ RhoA↑, E-cadherin↓ pERK1/2, phosphorylated ERK1/2; pAKT, phosphorylated AKT; CLL, chronic lymphocytic leukemia; pJNK, c-Jun N-terminal kinase; -, no change; ↑, upregulated; ↓, downregulated. ovarian cancer cells via the RhoA/ROCK/MLC signaling pathway [105] or E-cadherin [48].…”

Section: Altered Levels Of Ogt and O-glcnacylation In Cancers And Thementioning

confidence: 83%

“…Distinguishingly, O-GlcNAcylation is decreased in ovarian tumors compared with normal tissue [104]; however, O-GlcNAcylation augments the migration and invasion of SKOV3 and 59M [48,104,105] ↓/↓ migration↑, invasion↑ RhoA↑, E-cadherin↓ pERK1/2, phosphorylated ERK1/2; pAKT, phosphorylated AKT; CLL, chronic lymphocytic leukemia; pJNK, c-Jun N-terminal kinase; -, no change; ↑, upregulated; ↓, downregulated. ovarian cancer cells via the RhoA/ROCK/MLC signaling pathway [105] or E-cadherin [48].…”

Section: Altered Levels Of Ogt and O-glcnacylation In Cancers And Thementioning

confidence: 99%

Regulation and clinical significance of O-GlcNAc transferase in cancer

Zhang¹,

Gu²,

Yu³

et al. 2018

Oncotarget

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O-GlcNAc Transferase (OGT) resides in both cytosolic and nuclear compartments and catalyzes O-GlcNAcylation of myriad proteins. Numerous excellent reviews concerning roles of OGT in organismal and cellular physiology have exist, and aberrant OGT and protein O-GlcNAcylation have been implicated in progression and metastasis of different cancer types. Thus, understanding the regulation mechanisms of OGT and O-GlcNAcylation in tumor cells and their difference compared to non-tumor cells may elucidate new mechanisms related to tumor generation and development, could provide a new marker to diagnosis and prognosis in patients with cancer and indicate a new target to cancer chemotherapy. While it has become evident that OGT plays critical roles in cancers, it remains unclear how they are deregulated. This review provides an overview of our current knowledge about the known/potential regulation of OGT, and also discusses the inhibition of OGT as a potential novel therapeutic target for cancer treatment.

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O-GlcNAcylation promotes migration and invasion in human ovarian cancer cells via the RhoA/ROCK/MLC pathway

Cited by 26 publications

References 48 publications

Checkpoint kinase 1–induced phosphorylation of O-linked β-N-acetylglucosamine transferase regulates the intermediate filament network during cytokinesis

Checkpoint kinase 1–induced phosphorylation of O-linked β-N-acetylglucosamine transferase regulates the intermediate filament network during cytokinesis

Simulated microgravity inhibits cell focal adhesions leading to reduced melanoma cell proliferation and metastasis via FAK/RhoA-regulated mTORC1 and AMPK pathways

Regulation and clinical significance of O-GlcNAc transferase in cancer

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