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

Aram Ko, Su Yeon Han, Chel Hun Choi, Hanbyoul Cho, Min Sik Lee, Soo Youl Kim, Joon Seon Song, Kyeong Man Hong, Han Woong Lee, Stephen M. Hewitt, Joon Yong Chung, Jaewhan Song

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1050-1062
Number of pages13
JournalCell Death and Differentiation
Volume25
Issue number6
DOIs
Publication statusPublished - 2018 Jun 1

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Ubiquitin-Specific Proteases
Tumor Suppressor Protein p14ARF
Oncogenes
myc Genes
Protein Stability
Proteasome Endopeptidase Complex
Post Translational Protein Processing
Non-Small Cell Lung Carcinoma
Transcriptional Activation
Neoplasms
Fibroblasts
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Ko, Aram ; Han, Su Yeon ; Choi, Chel Hun ; Cho, Hanbyoul ; Lee, Min Sik ; Kim, Soo Youl ; Song, Joon Seon ; Hong, Kyeong Man ; Lee, Han Woong ; Hewitt, Stephen M. ; Chung, Joon Yong ; Song, Jaewhan. / Oncogene-induced senescence mediated by c-Myc requires USP10 dependent deubiquitination and stabilization of p14ARF. In: Cell Death and Differentiation. 2018 ; Vol. 25, No. 6. pp. 1050-1062.
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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.",
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Ko, A, Han, SY, Choi, CH, Cho, H, Lee, MS, Kim, SY, Song, JS, Hong, KM, Lee, HW, Hewitt, SM, Chung, JY & Song, J 2018, 'Oncogene-induced senescence mediated by c-Myc requires USP10 dependent deubiquitination and stabilization of p14ARF', Cell Death and Differentiation, vol. 25, no. 6, pp. 1050-1062. https://doi.org/10.1038/s41418-018-0072-0

Oncogene-induced senescence mediated by c-Myc requires USP10 dependent deubiquitination and stabilization of p14ARF. / Ko, Aram; Han, Su Yeon; Choi, Chel Hun; Cho, Hanbyoul; Lee, Min Sik; Kim, Soo Youl; Song, Joon Seon; Hong, Kyeong Man; Lee, Han Woong; Hewitt, Stephen M.; Chung, Joon Yong; Song, Jaewhan.

In: Cell Death and Differentiation, Vol. 25, No. 6, 01.06.2018, p. 1050-1062.

Research output: Contribution to journalArticle

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T1 - Oncogene-induced senescence mediated by c-Myc requires USP10 dependent deubiquitination and stabilization of p14ARF

AU - Ko, Aram

AU - Han, Su Yeon

AU - Choi, Chel Hun

AU - Cho, Hanbyoul

AU - Lee, Min Sik

AU - Kim, Soo Youl

AU - Song, Joon Seon

AU - Hong, Kyeong Man

AU - Lee, Han Woong

AU - Hewitt, Stephen M.

AU - Chung, Joon Yong

AU - Song, Jaewhan

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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.

AB - 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.

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