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 journalArticlepeer-review

11 Citations (Scopus)

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

Bibliographical note

Funding Information:
This work was supported by grants from the Basic Science Research Program of the National Research Foundation of Korea (NRF; 2014R1A1A1002589 to S. Han and A. Ko) and Creative Research Initiative Program of NRF (2015R1A3A2066581 to J. Song) funded by the Ministry of Science, ICT and Future Planning, and from the National Cancer Center, Korea (NCC-1420300 to J. Song). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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