Tid1-L inhibits EGFR signaling in lung adenocarcinoma by enhancing EGFR ubiquitinylation and degradation

Chi Yuan Chen, Chia Ing Jan, Jeng Fan Lo, Shuenn Chen Yang, Yih Leong Chang, Szu Hua Pan, Wen Lung Wang, Tse Ming Hong, Pan Chyr Yang

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Tid1 (DNAJA3), a DnaJ cochaperone, may promote degradation of oncogenic kinases. Tid1 has 2 isoforms, Tid1-L and Tid1-S, that may function differently. In this study, we investigated the role of the Tid1 isoforms in regulating EGF receptor (EGFR) signaling and lung cancer progression. We found that both Tid1-L and Tid1-S expressions were reduced in patients with non-small cell lung cancer compared with normal counterparts. Tid1-L expression correlated inversely with EGFR expression. Low Tid1-L/high EGFR expression predicted poor overall survival in patients with lung adenocarcinoma. Tid1-L overexpression in lung cancer cells attenuated EGFR signaling and inhibited cell proliferation, colony formation, and tumor growth in subcutaneous and orthotropic xenograft models. Conversely, depletion of Tid1 restored EGFR signaling and increased cell proliferation and colony formation. Tid1-L, but not Tid1-S, interacted with EGFR/HSP70/HSP90 through the DnaJ domain, counteracting the EGFR regulatory function of HSP90 by causing EGFR ubiquitinylation and proteasomal degradation. Tid1-L inhibited EGFR signaling even more than the HSP90 inhibitor 17-allylaminodemethoxy geldanamycin. We concluded that Tid1-L acted as a tumor suppressor by inhibiting EGFR signaling through interaction with EGFR/HSP70/HSP90 and enhancing EGFR ubiquitinylation and degradation.

Original languageEnglish
Pages (from-to)4009-4019
Number of pages11
JournalCancer Research
Volume73
Issue number13
DOIs
Publication statusPublished - 2013 Jul 1

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Epidermal Growth Factor Receptor
Adenocarcinoma of lung
Lung Neoplasms
Protein Isoforms
Cell Proliferation
Heterografts
Non-Small Cell Lung Carcinoma
Neoplasms
Phosphotransferases
Survival

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Chen, C. Y., Jan, C. I., Lo, J. F., Yang, S. C., Chang, Y. L., Pan, S. H., ... Yang, P. C. (2013). Tid1-L inhibits EGFR signaling in lung adenocarcinoma by enhancing EGFR ubiquitinylation and degradation. Cancer Research, 73(13), 4009-4019. https://doi.org/10.1158/0008-5472.CAN-12-4066
Chen, Chi Yuan ; Jan, Chia Ing ; Lo, Jeng Fan ; Yang, Shuenn Chen ; Chang, Yih Leong ; Pan, Szu Hua ; Wang, Wen Lung ; Hong, Tse Ming ; Yang, Pan Chyr. / Tid1-L inhibits EGFR signaling in lung adenocarcinoma by enhancing EGFR ubiquitinylation and degradation. In: Cancer Research. 2013 ; Vol. 73, No. 13. pp. 4009-4019.
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abstract = "Tid1 (DNAJA3), a DnaJ cochaperone, may promote degradation of oncogenic kinases. Tid1 has 2 isoforms, Tid1-L and Tid1-S, that may function differently. In this study, we investigated the role of the Tid1 isoforms in regulating EGF receptor (EGFR) signaling and lung cancer progression. We found that both Tid1-L and Tid1-S expressions were reduced in patients with non-small cell lung cancer compared with normal counterparts. Tid1-L expression correlated inversely with EGFR expression. Low Tid1-L/high EGFR expression predicted poor overall survival in patients with lung adenocarcinoma. Tid1-L overexpression in lung cancer cells attenuated EGFR signaling and inhibited cell proliferation, colony formation, and tumor growth in subcutaneous and orthotropic xenograft models. Conversely, depletion of Tid1 restored EGFR signaling and increased cell proliferation and colony formation. Tid1-L, but not Tid1-S, interacted with EGFR/HSP70/HSP90 through the DnaJ domain, counteracting the EGFR regulatory function of HSP90 by causing EGFR ubiquitinylation and proteasomal degradation. Tid1-L inhibited EGFR signaling even more than the HSP90 inhibitor 17-allylaminodemethoxy geldanamycin. We concluded that Tid1-L acted as a tumor suppressor by inhibiting EGFR signaling through interaction with EGFR/HSP70/HSP90 and enhancing EGFR ubiquitinylation and degradation.",
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Chen, CY, Jan, CI, Lo, JF, Yang, SC, Chang, YL, Pan, SH, Wang, WL, Hong, TM & Yang, PC 2013, 'Tid1-L inhibits EGFR signaling in lung adenocarcinoma by enhancing EGFR ubiquitinylation and degradation', Cancer Research, vol. 73, no. 13, pp. 4009-4019. https://doi.org/10.1158/0008-5472.CAN-12-4066

Tid1-L inhibits EGFR signaling in lung adenocarcinoma by enhancing EGFR ubiquitinylation and degradation. / Chen, Chi Yuan; Jan, Chia Ing; Lo, Jeng Fan; Yang, Shuenn Chen; Chang, Yih Leong; Pan, Szu Hua; Wang, Wen Lung; Hong, Tse Ming; Yang, Pan Chyr.

In: Cancer Research, Vol. 73, No. 13, 01.07.2013, p. 4009-4019.

Research output: Contribution to journalArticle

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AU - Pan, Szu Hua

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AU - Hong, Tse Ming

AU - Yang, Pan Chyr

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