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

Oncotarget
Angel ChaoHsin-Shih Wang

Abstract

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 ...Continue Reading

References

Dec 29, 2004·Cell·Stefan Kubicek, Thomas Jenuwein
Jul 6, 2007·Autophagy·Noboru Mizushima, Tamotsu Yoshimori
Aug 25, 2007·Nature Reviews. Molecular Cell Biology·M Chiara MaiuriGuido Kroemer
Sep 7, 2007·Nature·Jing HuangShelley L Berger
Jun 16, 2009·Cell·Jorge Moscat, Maria T Diaz-Meco
Jun 16, 2009·Cell·Robin MathewEileen White
Mar 25, 2010·International Journal of Cancer. Journal International Du Cancer·Shinya HayamiRyuji Hamamoto
Dec 30, 2011·Annals of Oncology : Official Journal of the European Society for Medical Oncology·R C Bast
Mar 20, 2012·Trends in Biochemical Sciences·Jorge Moscat, Maria T Diaz-Meco
Aug 28, 2012·Journal of the National Cancer Institute·Elisabetta KuhnIe-Ming Shih
Aug 29, 2012·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Angel ChaoHsin-Shih Wang
Jan 30, 2013·Proceedings of the National Academy of Sciences of the United States of America·Siming ZhaoAlessandro D Santin
Jul 23, 2013·Mutation Research·Diana L BordinJoão A P Henriques
Oct 15, 2013·Oncotarget·Franco VenanziAlexander Shneider
Jun 4, 2014·Genes & Development·Huijun WeiJun-Lin Guan
May 10, 2015·Journal of Ovarian Research·Cong ChenXuefeng Fang
May 21, 2015·Medicinal Research Reviews·Yi-Chao ZhengHong-Min Liu
Jul 15, 2015·International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society·Yun-Duo LiuXiu-Wei Chen
Nov 15, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Eileen WhiteChang S Chan
Jul 14, 2016·Oncotarget·Chia-Lung TsaiChyong-Huey Lai
Sep 7, 2016·Oncogene·E E MowersK F Macleod
Dec 4, 2016·Medical Science Monitor : International Medical Journal of Experimental and Clinical Research·Shujun FengJianhua Zheng

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Citations

Jul 1, 2020·Journal of Cellular and Molecular Medicine·Jiajun ZhouChaoqing Gao
Jul 17, 2020·Frontiers in Oncology·Anthony QuaglianoSonali P Barwe
Mar 21, 2020·Cellular and Molecular Life Sciences : CMLS·Feiying GuHuiyin Lan
Mar 28, 2018·Journal of Experimental Neuroscience·Susanna Ambrosio, Barbara Majello
Dec 16, 2020·Experimental & Molecular Medicine·Bruno PerilloAntimo Migliaccio
Jul 2, 2021·Frontiers in Cell and Developmental Biology·Yin ShiNancy Gordon
Aug 12, 2021·Journal of Medicinal Chemistry·Yang LiLiang Ouyang

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Methods Mentioned

BETA
transfection
co-immunoprecipitation
immunoprecipitation
confocal microscopy
proximity ligation assay
ubiquitination
xenograft
electrophoresis
PCR
ELISA

Software Mentioned

SPSS

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