Molecular chaperone HSP90 is necessary to prevent cellular senescence via lysosomal degradation of p14ARF

Su Yeon Han, Aram Ko, Haruhisa Kitano, Chel Hun Choi, Min Sik Lee, Jinho Seo, Junya Fukuoka, Soo Youl Kim, Stephen M. Hewitt, Joon Yong Chung, Jaewhan Song

Research output: Contribution to journalArticle

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Abstract

The tumor suppressor function of p14ARF is regulated at a posttranslational level via mechanisms yet to be fully understood. Here, we report the identification of an unconventional p14ARF degradation pathway induced by the chaperone HSP90 in association with the E3 ubiquitin ligase C-terminus of HSP70-interacting protein (CHIP). The ternary complex of HSP90, CHIP, and p14ARF was required to induce the lysosomal degradation of p14ARF by an ubiquitination-independent but LAMP2A-dependent mechanism. Depletion of HSP90 or CHIP induced p14ARF-dependent senescence in human fibroblasts. Premature senescence observed in cells genetically deficient in CHIP was rescued in cells that were doubly deficient in CHIP and p14ARF. Notably, non-smallcelllungcancercells (NSCLC) positive for p14ARF were sensitive to treatment with the HSP90 inhibitor geldanamycin. Furthermore, overexpression of HSP90 and CHIP with a concomitant loss of p14ARF correlated with poor prognosis in patients with NSCLC. Our findings identify a relationship between p14ARF and its chaperones that suggest new therapeutic strategies in cancers that overexpress HSP90.

Original languageEnglish
Pages (from-to)343-354
Number of pages12
JournalCancer Research
Volume77
Issue number2
DOIs
Publication statusPublished - 2017 Jan 15

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Tumor Suppressor Protein p14ARF
Molecular Chaperones
Cell Aging
Ubiquitin C
Proteins
Ubiquitin-Protein Ligases
Ubiquitination
Neoplasms
Fibroblasts

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Han, Su Yeon ; Ko, Aram ; Kitano, Haruhisa ; Choi, Chel Hun ; Lee, Min Sik ; Seo, Jinho ; Fukuoka, Junya ; Kim, Soo Youl ; Hewitt, Stephen M. ; Chung, Joon Yong ; Song, Jaewhan. / Molecular chaperone HSP90 is necessary to prevent cellular senescence via lysosomal degradation of p14ARF. In: Cancer Research. 2017 ; Vol. 77, No. 2. pp. 343-354.
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Han, SY, Ko, A, Kitano, H, Choi, CH, Lee, MS, Seo, J, Fukuoka, J, Kim, SY, Hewitt, SM, Chung, JY & Song, J 2017, 'Molecular chaperone HSP90 is necessary to prevent cellular senescence via lysosomal degradation of p14ARF', Cancer Research, vol. 77, no. 2, pp. 343-354. https://doi.org/10.1158/0008-5472.CAN-16-0613

Molecular chaperone HSP90 is necessary to prevent cellular senescence via lysosomal degradation of p14ARF. / Han, Su Yeon; Ko, Aram; Kitano, Haruhisa; Choi, Chel Hun; Lee, Min Sik; Seo, Jinho; Fukuoka, Junya; Kim, Soo Youl; Hewitt, Stephen M.; Chung, Joon Yong; Song, Jaewhan.

In: Cancer Research, Vol. 77, No. 2, 15.01.2017, p. 343-354.

Research output: Contribution to journalArticle

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AU - Seo, Jinho

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AU - Chung, Joon Yong

AU - Song, Jaewhan

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N2 - The tumor suppressor function of p14ARF is regulated at a posttranslational level via mechanisms yet to be fully understood. Here, we report the identification of an unconventional p14ARF degradation pathway induced by the chaperone HSP90 in association with the E3 ubiquitin ligase C-terminus of HSP70-interacting protein (CHIP). The ternary complex of HSP90, CHIP, and p14ARF was required to induce the lysosomal degradation of p14ARF by an ubiquitination-independent but LAMP2A-dependent mechanism. Depletion of HSP90 or CHIP induced p14ARF-dependent senescence in human fibroblasts. Premature senescence observed in cells genetically deficient in CHIP was rescued in cells that were doubly deficient in CHIP and p14ARF. Notably, non-smallcelllungcancercells (NSCLC) positive for p14ARF were sensitive to treatment with the HSP90 inhibitor geldanamycin. Furthermore, overexpression of HSP90 and CHIP with a concomitant loss of p14ARF correlated with poor prognosis in patients with NSCLC. Our findings identify a relationship between p14ARF and its chaperones that suggest new therapeutic strategies in cancers that overexpress HSP90.

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