title: Molecular Chaperone HSP90 Is Necessary to Prevent Cellular Senescence via Lysosomal Degradation of p14ARF.
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-small cell lung cancer cells (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. Cancer Res; 77(2); 343-54. ©2016 AACR.
authors: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea (South).
authors: Su Yeon
authors: SY
authors: Han
authors: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea (South).
authors: Aram
authors: A
authors: Ko
authors: Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.|Department of Thoracic Surgery, Shiga University of Medical Science, Otsu, Japan.
authors: Haruhisa
authors: H
authors: Kitano
authors: Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.|Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea (South).
authors: Chel Hun
authors: CH
authors: Choi
authors: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea (South).
authors: Min-Sik
authors: MS
authors: Lee
authors: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea (South).
authors: Jinho
authors: J
authors: Seo
authors: Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors: Junya
authors: J
authors: Fukuoka
authors: Cancer Cell and Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Republic of Korea (South).
authors: Soo-Youl
authors: SY
authors: Kim
authors: Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors: Stephen M
authors: SM
authors: Hewitt
authors: Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors: Joon-Yong
authors: JY
authors: Chung
authors: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea (South). jso678@yonsei.ac.kr.
authors: Jaewhan
authors: J
authors: Song
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D016922:Cellular Senescence / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016016:Proportional Hazards Models; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D018841:HSP90 Heat-Shock Proteins; D025803:Tumor Suppressor Protein p14ARF; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases