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

// Angel Chao 1, 2, * , Chiao-Yun Lin 1, 2, * , An-Ning Chao 3, * , Chia-Lung Tsai 4 , Ming-Yu Chen 1 , Li-Yu Lee 5 , Ting-Chang Chang 1, 2 , Tzu-Hao Wang 1, 2 , Chyong-Huey Lai 1, 2 and Hsin-Shih Wang 1 1 Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan 2 Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Kaohsiung, Taiwan 3 Department of Ophthalmology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan 4 Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan 5 Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan * These authors have contributed equally to this work Correspondence to: Tzu-Hao Wang, email: knoxtn@cgmh.org.tw Chyong-Huey Lai, email: sh46erry@ms6.hinet.net Keywords: gynecologic malignancies, LSD1, autophagy, p62 Received: October 25, 2016 Accepted: June 19, 2017 Published: August 10, 2017 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.