Lysine-specific demethylase 1 (LSD1) destabilizes p62 and inhibits autophagy in gynecologic malignancies
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Angel Chao1,2,*, Chiao-Yun Lin1,2,*, An-Ning Chao3,*, Chia-Lung Tsai4, Ming-Yu Chen1, Li-Yu Lee5, Ting-Chang Chang1,2, Tzu-Hao Wang1,2, Chyong-Huey Lai1,2 and Hsin-Shih Wang1
1Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
2Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Kaohsiung, Taiwan
3Department of Ophthalmology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
4Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan
5Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
*These authors have contributed equally to this work
Tzu-Hao Wang, email: [email protected]
Chyong-Huey Lai, email: [email protected]
Keywords: gynecologic malignancies, LSD1, autophagy, p62
Received: October 25, 2016 Accepted: June 19, 2017 Published: August 10, 2017
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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