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Oncogene-induced senescence mediated by c-Myc requires USP10 dependent deubiquitination and stabilization of p14ARF.

ABSTRACT: Oncogene-induced senescence (OIS) is a critical tumor-suppressor mechanism, which prevents hyper-proliferation and transformation of cells. c-Myc promotes OIS through the transcriptional activation of p14ARF followed by p53 activation. Although the oncogene-mediated transcriptional regulation of p14ARF has been well addressed, the post-translational modification of p14ARF regulated by oncogenic stress has yet to be investigated. Here, we found that c-Myc increased p14ARF protein stability by inducing the transcription of ubiquitin-specific protease 10 (USP10). USP10, in turn, mediated the deubiquitination of p14ARF, preventing its proteasome-dependent degradation. USP10-null mouse embryonic fibroblasts and human primary cells depleted of USP10 bypassed c-Myc-induced senescence via the destabilization of p14ARF, and these cells displayed accelerated hyper-proliferation and transformation. Clinically the c-Myc-USP10-p14ARF axis was disrupted in non-small cell lung cancer patients, resulting in significantly worse overall survival. Our studies indicate that USP10 induced by c-Myc has a crucial role in OIS by maintaining the stability of key tumor suppressor p14ARF.

SUBMITTER: Ko A

PROVIDER: S-EPMC5988833 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Oncogene-induced senescence mediated by c-Myc requires USP10 dependent deubiquitination and stabilization of p14ARF.

Ko Aram A Han Su Yeon SY Choi Chel Hun CH Cho Hanbyoul H Lee Min-Sik MS Kim Soo-Youl SY Song Joon Seon JS Hong Kyeong-Man KM Lee Han-Woong HW Hewitt Stephen M SM Chung Joon-Yong JY Song Jaewhan J

Cell death and differentiation 20180222 6

Oncogene-induced senescence (OIS) is a critical tumor-suppressor mechanism, which prevents hyper-proliferation and transformation of cells. c-Myc promotes OIS through the transcriptional activation of p14ARF followed by p53 activation. Although the oncogene-mediated transcriptional regulation of p14ARF has been well addressed, the post-translational modification of p14ARF regulated by oncogenic stress has yet to be investigated. Here, we found that c-Myc increased p14ARF protein stability by ind ...[more]

PMID: 29472714

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Project description:BackgroundOsteosarcoma (OS) is recognized as a prevalent primary bone malignancy, particularly affecting adolescents during their growth spurts. Despite its clinical significance, the underlying biological characteristics and associated prognostic factors remain incompletely understood. The identification of novel molecular players involved in osteosarcoma progression could enhance our understanding of its pathogenesis and potentially inform patient management strategies.MethodsIn this study, we investigated the expression levels of Spindle and Centriole-Associated Protein 1 (SPICE1) in OS cells and tissues through quantitative analyses. We performed in vitro and in vivo experiments to evaluate the proliferation effects of SPICE1 on OS cells. Additionally, we explored the mechanistic interactions between SPICE1, Fatty Acid Synthase (FASN), and ubiquitin-specific peptidase 10 (USP10) through co-immunoprecipitation and mutation analyses, including the design of a peptide to inhibit the SPICE1-FASN interaction.ResultsOur findings revealed that SPICE1 is significantly overexpressed in OS samples. Furthermore, this high expression correlates with poor patient prognosis. The elevated levels of SPICE1 were found to promote OS cell proliferation by inhibiting the ubiquitination of FASN, consequently enhancing FASN protein stability. Additionally, SPICE1 was shown to facilitate the interaction between USP10 and FASN, promoting FASN deubiquitination, with specific amino acid interactions identified between USP10 and FASN that are necessary for this process.ConclusionThis study elucidates the role of SPICE1 as a potential oncogene in OS, highlighting its contribution to tumor growth through the modulation of FASN stability. Importantly, our results suggest that targeting the SPICE1/USP10/FASN signaling axis could offer a novel therapeutic approach for treating OS. Future investigations should focus on the development of specific inhibitors that disrupt this pathway, ultimately leading to improved clinical outcomes for patients with OS.

Dataset Information

Oncogene-induced senescence mediated by c-Myc requires USP10 dependent deubiquitination and stabilization of p14ARF.

Publications

Oncogene-induced senescence mediated by c-Myc requires USP10 dependent deubiquitination and stabilization of p14ARF.

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