The Lysine-specific Demethylase 1 Is Required for Cell Proliferation in Both p53-dependent and -independent Manners

Abstract

The lysine-specific demethylase 1 (LSD1), a component of several histone deacetylase complexes, plays an important role in chromatin remodeling and transcriptional regulation. Here, we generated multiple cell lines in which LSD1 is inducibly expressed or knocked down and found that LSD1 is required for cell proliferation. In addition, we found that deficiency in LSD1 leads to a partial cell cycle arrest in G 2 /M and sensitizes cells to growth suppression induced by DNA damage or MDM2 inhibition in a p53-dependent manner. We also showed that LSD1 deficiency delays p53 stabilization induced by DNA damage, leading to a delayed induction of p21 and MDM2. Finally, we performed a microarray study and identified several novel LSD1 target genes, including S100A8, which encodes a calcium-binding protein, and DEK, a proto-oncogene. Taken together, we uncovered that LSD1 has a pro-oncogenic function by modulating pro-survival gene expression and p53 transcriptional activity.Modifications of histones, including acetylation, methylation, and phosphorylation, play a major role in the regulation of chromatin structure and gene transcription (1). The lysine-specific demethylase (LSD1/BHC110) and JmjC domain-containing family members are histone lysine demethylases (2, 3). LSD1, 2 a nuclear homolog of amine oxidases, uses a flavin-dependent oxidation reaction to demethylate histone H3 at lysine 4 and induce transcriptional repression (2). Indeed, LSD1 is a component of several histone deacetylase co-repressor complexes, including histone deacetylase (HDAC), CtBP, and the neuronal CoREST complexes (4 -6). In addition, LSD1 is found to promote androgen-receptordependent gene activation by demethylation of histone H3 at lysine 9 (7). Thus, LSD1 has a dual role in transcriptional activation and repression.A few non-histone proteins are found to be methylated at lysine residues, such as TAF10 and p53 (8,9). In response to stress signals, p53 is stabilized and plays an essential role in the induction of cell cycle arrest, apoptosis, or its own regulation (10). Interestingly, lysine methylation has varied effect on p53 function: methylation at lysine 372 by Set9 activates p53 transcriptional activity and methylation at lysine 370 by Smyd2 represses it (9, 11). Furthermore, our earlier study indicates that p53 represses specific target genes via protein methyltransferases (12). The effect of LSD1 on non-histone protein function is yet unknown.

The histone demethylase LSD1/KDM1A promotes the DNA damage response

“…Numerous studies have suggested that RNF168 plays an important role in the recruitment of 53BP1 to sites of DNA damage the cell cycle distribution of cells upon LSD1 knockdown, as this was unchanged relative to control knockdown cells, consistent with previously published data (Scoumanne and Chen, 2007;unpublished data).…”

Pomalidomide and Lenalidomide Induce p21WAF-1 Expression in Both Lymphoma and Multiple Myeloma through a LSD1-Mediated Epigenetic Mechanism

“…LSD1-dependent transcriptional activation is not restricted to androgen receptor function in prostate cancer cells because a genome-wide location analysis of LSD1 in MCF7 human breast cancer cells reported a surprisingly large number of promoters bound to LSD1, among which 84% were also associated with RNA polymerase II (48), underlining the importance of LSD1 in gene activation. LSD1 has already been reported to up-regulate p21 WAF-1 through p53 stabilization (49). Our study describes for the first time that LSD1 participates in p21 WAF-1 transcription in a p53-independent manner.…”

DEK oncoprotein regulates transcriptional modifiers and sustains tumor initiation activity in high-grade neuroendocrine carcinoma of the lung

“…DEK expression is regulated by E2F and overexpression of DEK protein has been reported in several types of solid tumor (Carro et al, 2006). Moreover, DEK inhibits apoptosis by modulating p53 activity and is implicated in cellular senescence/ immortalization (Wise-Draper et al, 2006;Scoumanne and Chen, 2007). It has been reported that DEK has transforming activity in human keratinocytes when working in association with HPV E6/E7 viral oncoproteins or p16 silencing (Wise-Draper et al, 2005, 2009a.…”

“…As DEK is widely expressed in primary HGNEC, an arising question is how DEK specifically regulates a set of genes in distinct cellular contexts, such as CSC. One possibility is that additional modification of DEK might determine its target specificity (Kappes et al, 2004;Scoumanne and Chen, 2007). Another, but not exclusive, idea is that additional cooperation with other transcriptional factors or nucleosome/chromatin assembly factors may mark specific DEK binding or work cooperatively and induce characteristic transcriptional changes, as DEK has been shown to interact with several epigenetic modifiers (Hollenbach et al, 2002;Cleary et al, 2005;Cavella´n et al, 2006).…”