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14-3-3? targeting induced senescence in Hep-2 laryngeal cancer cell through deneddylation of Cullin1 in the Skp1-Cullin-F-box protein complex.

ABSTRACT: OBJECTIVES:Despite of the aberrant expression of 14-3-3? in head and neck squamous cell carcinoma (HNSCC), little is known about the role of 14-3-3? in the regulation of senescence in HNSCC. This study was performed to investigate whether 14-3-3? is implicated in senescence evasion of Hep-2 laryngeal cancer cells. METHODS:The expression of 14-3-3? was suppressed using RNA interference strategy. Senescence induction was determined by senescence-associated ?-galactosidase staining and the numbers of promyelocytic leukaemia nuclear body. Real-time PCR, western blotting and immunohistochemistry were applied for the expression of corresponding proteins. Xenograft experiment was performed to show in vivo effect of 14-3-3? silencing on tumour growth. RESULTS:14-3-3? silencing significantly induced senescence phenotypes via 27 accumulations. Subsequently, we demonstrated that p27 accumulation is linked to inactivation of SCFSkp2 complex activity, probably due to the deneddylation of cullin-1 (Cul-1) as follows. (a) Neddylated Cul-1 is decreased by 14-3-3? silencing. (b) Blocking neddylation using MLN4924 reproduces senescence phenotypes. (c) Knockdown of CSN5, which functions as a deneddylase, was shown to restore the senescence phenotypes induced by 14-3-3? depletion. Finally, we demonstrated that 14-3-3? depletion effectively hindered the proliferation of Hep-2 cells implanted into nude mice. CONCLUSION:14-3-3? negatively regulates senescence in Hep-2 cells, suggesting that 14-3-3? targeting may serve to suppress the expansion of laryngeal cancer via induction of senescence through the Cul-1/SCFSkp2 /p27 axis.

SUBMITTER: Seo SB

PROVIDER: S-EPMC6797561 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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14-3-3ζ targeting induced senescence in Hep-2 laryngeal cancer cell through deneddylation of Cullin1 in the Skp1-Cullin-F-box protein complex.

Seo Sung Bin SB Baek Ji-Ye JY Lim Ji-Hee JH Jin Xuyan X Lee Mun-Yong MY Lee Jeong-Hwa JH

Cell proliferation 20190621 5

<h4>Objectives</h4>Despite of the aberrant expression of 14-3-3ζ in head and neck squamous cell carcinoma (HNSCC), little is known about the role of 14-3-3ζ in the regulation of senescence in HNSCC. This study was performed to investigate whether 14-3-3ζ is implicated in senescence evasion of Hep-2 laryngeal cancer cells.<h4>Methods</h4>The expression of 14-3-3ζ was suppressed using RNA interference strategy. Senescence induction was determined by senescence-associated β-galactosidase staining a ...[more]

PMID: 31222857

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Project description:Cardiomyocyte death in the form of apoptosis and necrosis represents a major cellular mechanism underlying cardiac pathogenesis. Recent advances in cell death research reveal that not all necrosis is accidental, but rather there are multiple forms of necrosis that are regulated. Necroptosis, the earliest identified regulated necrosis, is perhaps the most studied thus far, and potential links between necroptosis and Cullin-RING ligases (CRLs), the largest family of ubiquitin E3 ligases, have been postulated. Cullin neddylation activates the catalytic dynamic of CRLs; the reverse process, Cullin deneddylation, is performed by the COP9 signalosome holocomplex (CSN) that is formed by eight unique protein subunits, COPS1/CNS1 through COPS8/CNS8. As revealed by cardiomyocyte-restricted knockout of Cops8 (Cops8-cko) in mice, perturbation of Cullin deneddylation in cardiomyocytes impairs not only the functioning of the ubiquitin-proteasome system (UPS) but also the autophagic-lysosomal pathway (ALP). Similar cardiac abnormalities are also observed in Cops6-cko mice; and importantly, loss of the desmosome targeting of COPS6 is recently implicated as a pathogenic factor in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Cops8-cko causes massive cardiomyocyte death in the form of necrosis rather than apoptosis and rapidly leads to a progressive dilated cardiomyopathy phenotype as well as drastically shortened lifespan in mice. Even a moderate downregulation of Cullin deneddylation as seen in mice with Cops8 hypomorphism exacerbates cardiac proteotoxicity induced by overexpression of misfolded proteins. More recently, it was further demonstrated that cardiomyocyte necrosis caused by Cops8-cko belongs to necroptosis and is mediated by the RIPK1-RIPK3 pathway. This article reviews these recent advances and discusses the potential links between Cullin deneddylation and the necroptotic pathways in hopes of identifying potentially new therapeutic targets for the prevention of cardiomyocyte death.

Dataset Information

14-3-3? targeting induced senescence in Hep-2 laryngeal cancer cell through deneddylation of Cullin1 in the Skp1-Cullin-F-box protein complex.

Publications

14-3-3ζ targeting induced senescence in Hep-2 laryngeal cancer cell through deneddylation of Cullin1 in the Skp1-Cullin-F-box protein complex.

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