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Lysine-specific demethylase 1 (LSD1) destabilizes p62 and inhibits autophagy in gynecologic malignancies

Lysine-specific demethylase 1 (LSD1) – also known as KDM1A – is the first identified histone demethylase. LSD1 is highly expressed in numerous human malignancies and has recently emerged as a target for anticancer drugs. Owing to the presence of several functional domains, we speculated that LSD1 co...

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Autores principales: Chao, Angel, Lin, Chiao-Yun, Chao, An-Ning, Tsai, Chia-Lung, Chen, Ming-Yu, Lee, Li-Yu, Chang, Ting-Chang, Wang, Tzu-Hao, Lai, Chyong-Huey, Wang, Hsin-Shih
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650353/
https://www.ncbi.nlm.nih.gov/pubmed/29088798
http://dx.doi.org/10.18632/oncotarget.20158
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author Chao, Angel
Lin, Chiao-Yun
Chao, An-Ning
Tsai, Chia-Lung
Chen, Ming-Yu
Lee, Li-Yu
Chang, Ting-Chang
Wang, Tzu-Hao
Lai, Chyong-Huey
Wang, Hsin-Shih
author_facet Chao, Angel
Lin, Chiao-Yun
Chao, An-Ning
Tsai, Chia-Lung
Chen, Ming-Yu
Lee, Li-Yu
Chang, Ting-Chang
Wang, Tzu-Hao
Lai, Chyong-Huey
Wang, Hsin-Shih
author_sort Chao, Angel
collection PubMed
description Lysine-specific demethylase 1 (LSD1) – also known as KDM1A – is the first identified histone demethylase. LSD1 is highly expressed in numerous human malignancies and has recently emerged as a target for anticancer drugs. Owing to the presence of several functional domains, we speculated that LSD1 could have additional functions other than histone demethylation. P62 – also termed sequestasome 1 (SQSTM1) – plays a key role in malignant transformation, apoptosis, and autophagy. Here, we show that a high LSD1 expression promotes tumorigenesis in gynecologic malignancies. Notably, LSD1 inhibition with either siRNA or pharmacological agents activates autophagy. Mechanistically, LSD1 decreases p62 protein stability in a demethylation-independent manner. Inhibition of LSD1 reduces both tumor growth and p62 protein degradation in vivo. The combination of LSD1 inhibition and p62 knockdown exerts additive anticancer effects. We conclude that LSD1 destabilizes p62 and inhibits autophagy in gynecologic cancers. LSD1 inhibition reduces malignant cell growth and activates autophagy. The combinations of LSD1 inhibition and autophagy blockade display additive inhibitory effect on cancer cell viability. A better understanding of the role played by p62 will shed more light on the anticancer effects of LSD1 inhibitors.
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spelling pubmed-56503532017-10-30 Lysine-specific demethylase 1 (LSD1) destabilizes p62 and inhibits autophagy in gynecologic malignancies Chao, Angel Lin, Chiao-Yun Chao, An-Ning Tsai, Chia-Lung Chen, Ming-Yu Lee, Li-Yu Chang, Ting-Chang Wang, Tzu-Hao Lai, Chyong-Huey Wang, Hsin-Shih Oncotarget Research Paper Lysine-specific demethylase 1 (LSD1) – also known as KDM1A – is the first identified histone demethylase. LSD1 is highly expressed in numerous human malignancies and has recently emerged as a target for anticancer drugs. Owing to the presence of several functional domains, we speculated that LSD1 could have additional functions other than histone demethylation. P62 – also termed sequestasome 1 (SQSTM1) – plays a key role in malignant transformation, apoptosis, and autophagy. Here, we show that a high LSD1 expression promotes tumorigenesis in gynecologic malignancies. Notably, LSD1 inhibition with either siRNA or pharmacological agents activates autophagy. Mechanistically, LSD1 decreases p62 protein stability in a demethylation-independent manner. Inhibition of LSD1 reduces both tumor growth and p62 protein degradation in vivo. The combination of LSD1 inhibition and p62 knockdown exerts additive anticancer effects. We conclude that LSD1 destabilizes p62 and inhibits autophagy in gynecologic cancers. LSD1 inhibition reduces malignant cell growth and activates autophagy. The combinations of LSD1 inhibition and autophagy blockade display additive inhibitory effect on cancer cell viability. A better understanding of the role played by p62 will shed more light on the anticancer effects of LSD1 inhibitors. Impact Journals LLC 2017-08-10 /pmc/articles/PMC5650353/ /pubmed/29088798 http://dx.doi.org/10.18632/oncotarget.20158 Text en Copyright: © 2017 Chao et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Chao, Angel
Lin, Chiao-Yun
Chao, An-Ning
Tsai, Chia-Lung
Chen, Ming-Yu
Lee, Li-Yu
Chang, Ting-Chang
Wang, Tzu-Hao
Lai, Chyong-Huey
Wang, Hsin-Shih
Lysine-specific demethylase 1 (LSD1) destabilizes p62 and inhibits autophagy in gynecologic malignancies
title Lysine-specific demethylase 1 (LSD1) destabilizes p62 and inhibits autophagy in gynecologic malignancies
title_full Lysine-specific demethylase 1 (LSD1) destabilizes p62 and inhibits autophagy in gynecologic malignancies
title_fullStr Lysine-specific demethylase 1 (LSD1) destabilizes p62 and inhibits autophagy in gynecologic malignancies
title_full_unstemmed Lysine-specific demethylase 1 (LSD1) destabilizes p62 and inhibits autophagy in gynecologic malignancies
title_short Lysine-specific demethylase 1 (LSD1) destabilizes p62 and inhibits autophagy in gynecologic malignancies
title_sort lysine-specific demethylase 1 (lsd1) destabilizes p62 and inhibits autophagy in gynecologic malignancies
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650353/
https://www.ncbi.nlm.nih.gov/pubmed/29088798
http://dx.doi.org/10.18632/oncotarget.20158
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