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.
Highlights
Methylation is a form of post-translational covalent modification of histones that epigenetically regulates specific gene expression patterns
Growing evidence indicates that Lysine-specific demethylase 1 (LSD1) is critical for human tumorigenesis, and its expression is increased in several malignancies – including bladder cancer [3], prostate cancer [4], non-small cell lung cancer [5], breast cancer [6, 7], colon cancer [8], uterine endometrioid adenocarcinoma [9, 10], as well as www.impactjournals.com/oncotarget ovarian serous and mucinous adenocarcinomas [11,12,13,14]
Our results indicate that LSD1 is capable of interacting and stabilizing the selective autophagy substrate p62 (Figure 8)
Summary
Methylation is a form of post-translational covalent modification of histones that epigenetically regulates specific gene expression patterns. Lysine-specific demethylase 1 (LSD1; known as KDM1A; Gene ID 23028) – the first identified histone demethylase – is a monoamine oxidase (MAO) homologue that demethylates mono- or dimethylated histone H3 lysine 4 (H3K4) and H3 lysine 9 (H3K9) through amine oxidation [1]. As a flavin adenine dinucleotide (FAD)-dependent enzyme, LSD1 consists of three major domains − an N-terminal SWIRM domain, a central protruding tower domain, and a C-terminal amine oxidase like (AOL) domain [2]. Epidermal growth factor has been shown to stimulate LSD1 expression [13], which in turn promotes epithelialmesenchymal transition [14]. Owing to the presence of several functional domains, we speculate that LSD1 could have additional functions other than histone demethylation
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