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

Angel Chao, Chiao Yun Lin, An Ning Chao, Chia Lung Tsai, Ming Yu Chen, Li Yu Lee, Ting Chang Chang, Tzu Hao Wang*, Chyong Huey Lai, Hsin Shih Wang

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

41 Scopus citations

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 by p62 will shed more light on the anticancer effects of LSD1 inhibitors.

Original languageEnglish
Pages (from-to)74434-74450
Number of pages17
JournalOncotarget
Volume8
Issue number43
DOIs
StatePublished - 2017

Bibliographical note

Publisher Copyright:
© Chao et al.

Keywords

  • Autophagy
  • Gynecologic malignancies
  • LSD1
  • P62

Fingerprint

Dive into the research topics of 'Lysine-specific demethylase 1 (LSD1) destabilizes p62 and inhibits autophagy in gynecologic malignancies'. Together they form a unique fingerprint.

Cite this