Downregulation of CHIP promotes ovarian cancer metastasis by inducing Snail-mediated epithelial–mesenchymal transition

Sun Mi Park; Seung Ho Park; Ki Jun Ryu; In Kyu Kim; Hyeontak Han; Hyo Jin Kim; Seon Hee Kim; Keun Seok Hong; Hyemin Kim; Minju Kim; Bok Im Cho; Jeong Doo Heo; Na Hyun Kim; Eun Mi Hwang; Jae Yong Park; Jong In Yook; Hee Jun Cho; Cheol Hwangbo; Kwang Dong Kim; Hoseok Song; Jiyun Yoo

doi:10.1002/1878-0261.12485

Downregulation of CHIP promotes ovarian cancer metastasis by inducing Snail-mediated epithelial–mesenchymal transition

Sun Mi Park, Seung Ho Park, Ki Jun Ryu, In Kyu Kim, Hyeontak Han, Hyo Jin Kim, Seon Hee Kim, Keun Seok Hong, Hyemin Kim, Minju Kim, Bok Im Cho, Jeong Doo Heo, Na Hyun Kim, Eun Mi Hwang, Jae Yong Park, Jong In Yook, Hee Jun Cho, Cheol Hwangbo, Kwang Dong Kim, Hoseok SongJiyun Yoo

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

Abstract

The epithelial–mesenchymal transition (EMT) plays a pivotal role in the conversion of early-stage tumors into invasive malignancies. The transcription factor Snail, an extremely unstable protein whose subcellular levels are regulated by many E3 ubiquitin ligases, promotes EMT as well as associated pathological characteristics including migration, invasion, and metastasis. Through yeast two-hybrid screening, we identified the carboxyl terminus of Hsc70-interacting protein (CHIP) as a novel Snail ubiquitin ligase that interacts with Snail to induce ubiquitin-mediated proteasomal degradation. Inhibition of CHIP expression increases Snail protein levels, induces EMT, and enhances in vitro migration and invasion as well as in vivo metastasis of ovarian cancer cells. In turn, Snail depletion abrogates all phenomena induced by CHIP depletion. Finally, Snail and CHIP expression is inversely correlated in ovarian tumor tissues. These findings establish the CHIP–Snail axis as a post-translational mechanism of EMT and cancer metastasis regulation.

Original language	English
Pages (from-to)	1280-1295
Number of pages	16
Journal	Molecular Oncology
Volume	13
Issue number	5
DOIs	https://doi.org/10.1002/1878-0261.12485
Publication status	Published - 2019 May

Keywords

CHIP
E3 ubiquitin ligase
EMT
cancer metastasis
ovarian cancer
snail

ASJC Scopus subject areas

Molecular Medicine
Oncology
Genetics
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/1878-0261.12485

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Park, S. M., Park, S. H., Ryu, K. J., Kim, I. K., Han, H., Kim, H. J., Kim, S. H., Hong, K. S., Kim, H., Kim, M., Cho, B. I., Heo, J. D., Kim, N. H., Hwang, E. M., Park, J. Y., Yook, J. I., Cho, H. J., Hwangbo, C., Kim, K. D., ... Yoo, J. (2019). Downregulation of CHIP promotes ovarian cancer metastasis by inducing Snail-mediated epithelial–mesenchymal transition. Molecular Oncology, 13(5), 1280-1295. https://doi.org/10.1002/1878-0261.12485

Park, SM, Park, SH, Ryu, KJ, Kim, IK, Han, H, Kim, HJ, Kim, SH, Hong, KS, Kim, H, Kim, M, Cho, BI, Heo, JD, Kim, NH, Hwang, EM, Park, JY, Yook, JI, Cho, HJ, Hwangbo, C, Kim, KD, Song, H & Yoo, J 2019, 'Downregulation of CHIP promotes ovarian cancer metastasis by inducing Snail-mediated epithelial–mesenchymal transition', Molecular Oncology, vol. 13, no. 5, pp. 1280-1295. https://doi.org/10.1002/1878-0261.12485

@article{523f2b9d9a4a474b9056b3840a2fce8d,

title = "Downregulation of CHIP promotes ovarian cancer metastasis by inducing Snail-mediated epithelial–mesenchymal transition",

abstract = "The epithelial–mesenchymal transition (EMT) plays a pivotal role in the conversion of early-stage tumors into invasive malignancies. The transcription factor Snail, an extremely unstable protein whose subcellular levels are regulated by many E3 ubiquitin ligases, promotes EMT as well as associated pathological characteristics including migration, invasion, and metastasis. Through yeast two-hybrid screening, we identified the carboxyl terminus of Hsc70-interacting protein (CHIP) as a novel Snail ubiquitin ligase that interacts with Snail to induce ubiquitin-mediated proteasomal degradation. Inhibition of CHIP expression increases Snail protein levels, induces EMT, and enhances in vitro migration and invasion as well as in vivo metastasis of ovarian cancer cells. In turn, Snail depletion abrogates all phenomena induced by CHIP depletion. Finally, Snail and CHIP expression is inversely correlated in ovarian tumor tissues. These findings establish the CHIP–Snail axis as a post-translational mechanism of EMT and cancer metastasis regulation.",

keywords = "CHIP, E3 ubiquitin ligase, EMT, cancer metastasis, ovarian cancer, snail",

author = "Park, {Sun Mi} and Park, {Seung Ho} and Ryu, {Ki Jun} and Kim, {In Kyu} and Hyeontak Han and Kim, {Hyo Jin} and Kim, {Seon Hee} and Hong, {Keun Seok} and Hyemin Kim and Minju Kim and Cho, {Bok Im} and Heo, {Jeong Doo} and Kim, {Na Hyun} and Hwang, {Eun Mi} and Park, {Jae Yong} and Yook, {Jong In} and Cho, {Hee Jun} and Cheol Hwangbo and Kim, {Kwang Dong} and Hoseok Song and Jiyun Yoo",

note = "Funding Information: We thank Professor Yunjin Jung at Pusan National University for the kind gift of CHIP-∆TPR, CHIP-∆U-box, CHIP-K30A, and CHIP-H260Q constructs. This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Ministry of Education (NRF-2013R1A1A2057753) and the Korean government (MSIP) (NRF-2017R1A2B4003185). Publisher Copyright: {\textcopyright} 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.",

year = "2019",

month = may,

doi = "10.1002/1878-0261.12485",

language = "English",

volume = "13",

pages = "1280--1295",

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T1 - Downregulation of CHIP promotes ovarian cancer metastasis by inducing Snail-mediated epithelial–mesenchymal transition

AU - Park, Sun Mi

AU - Park, Seung Ho

AU - Ryu, Ki Jun

AU - Kim, In Kyu

AU - Han, Hyeontak

AU - Kim, Hyo Jin

AU - Kim, Seon Hee

AU - Hong, Keun Seok

AU - Kim, Hyemin

AU - Kim, Minju

AU - Cho, Bok Im

AU - Heo, Jeong Doo

AU - Kim, Na Hyun

AU - Hwang, Eun Mi

AU - Park, Jae Yong

AU - Yook, Jong In

AU - Cho, Hee Jun

AU - Hwangbo, Cheol

AU - Kim, Kwang Dong

AU - Song, Hoseok

AU - Yoo, Jiyun

N1 - Funding Information: We thank Professor Yunjin Jung at Pusan National University for the kind gift of CHIP-∆TPR, CHIP-∆U-box, CHIP-K30A, and CHIP-H260Q constructs. This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Ministry of Education (NRF-2013R1A1A2057753) and the Korean government (MSIP) (NRF-2017R1A2B4003185). Publisher Copyright: © 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

PY - 2019/5

Y1 - 2019/5

N2 - The epithelial–mesenchymal transition (EMT) plays a pivotal role in the conversion of early-stage tumors into invasive malignancies. The transcription factor Snail, an extremely unstable protein whose subcellular levels are regulated by many E3 ubiquitin ligases, promotes EMT as well as associated pathological characteristics including migration, invasion, and metastasis. Through yeast two-hybrid screening, we identified the carboxyl terminus of Hsc70-interacting protein (CHIP) as a novel Snail ubiquitin ligase that interacts with Snail to induce ubiquitin-mediated proteasomal degradation. Inhibition of CHIP expression increases Snail protein levels, induces EMT, and enhances in vitro migration and invasion as well as in vivo metastasis of ovarian cancer cells. In turn, Snail depletion abrogates all phenomena induced by CHIP depletion. Finally, Snail and CHIP expression is inversely correlated in ovarian tumor tissues. These findings establish the CHIP–Snail axis as a post-translational mechanism of EMT and cancer metastasis regulation.

AB - The epithelial–mesenchymal transition (EMT) plays a pivotal role in the conversion of early-stage tumors into invasive malignancies. The transcription factor Snail, an extremely unstable protein whose subcellular levels are regulated by many E3 ubiquitin ligases, promotes EMT as well as associated pathological characteristics including migration, invasion, and metastasis. Through yeast two-hybrid screening, we identified the carboxyl terminus of Hsc70-interacting protein (CHIP) as a novel Snail ubiquitin ligase that interacts with Snail to induce ubiquitin-mediated proteasomal degradation. Inhibition of CHIP expression increases Snail protein levels, induces EMT, and enhances in vitro migration and invasion as well as in vivo metastasis of ovarian cancer cells. In turn, Snail depletion abrogates all phenomena induced by CHIP depletion. Finally, Snail and CHIP expression is inversely correlated in ovarian tumor tissues. These findings establish the CHIP–Snail axis as a post-translational mechanism of EMT and cancer metastasis regulation.

KW - CHIP

KW - E3 ubiquitin ligase

KW - EMT

KW - cancer metastasis

KW - ovarian cancer

KW - snail

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U2 - 10.1002/1878-0261.12485

DO - 10.1002/1878-0261.12485

M3 - Article

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AN - SCOPUS:85065021617

SN - 1574-7891

VL - 13

SP - 1280

EP - 1295

JO - Molecular Oncology

JF - Molecular Oncology

IS - 5

ER -

Downregulation of CHIP promotes ovarian cancer metastasis by inducing Snail-mediated epithelial–mesenchymal transition

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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