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Originally published In Press as doi:10.1074/jbc.M701023200 on April 4, 2007

J. Biol. Chem., Vol. 282, Issue 21, 15471-15475, May 25, 2007
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The Lysine-specific Demethylase 1 Is Required for Cell Proliferation in Both p53-dependent and -independent Manners*

Ariane Scoumanne{ddagger}§ and Xinbin Chen{ddagger}§1

From the {ddagger}Center for Comparative Oncology, University of California at Davis, Davis, California 95616 and the §Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294

Received for publication, February 2, 2007 , and in revised form, April 3, 2007.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 EXPERIMENTAL PROCEDURES
 RESULTS
 DISCUSSION
 REFERENCES
 
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 G2/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.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
EXPERIMENTAL PROCEDURES
 RESULTS
 DISCUSSION
 REFERENCES
 
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-receptor-dependent 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.


   EXPERIMENTAL PROCEDURES
TOP
 ABSTRACT
 INTRODUCTION
 EXPERIMENTAL PROCEDURES
RESULTS
 DISCUSSION
 REFERENCES
 
Reagents—Nutlin-3 was purchased from Cayman Chemical Company. Anti-glyceraldehyde-3-phosphate dehydrogenase (GAPDH), anti-p21, and anti-MDM2 (SMP14) antibodies were from Santa Cruz Biotechnology (Santa Cruz, CA). Anti-LSD1 antibody was from Abcam (Cambridge, MA). Anti-hemagglutinin (HA) and anti-MDM2 (Ab-2) were from Covance (Berkeley, CA) and EMB Biosciences (San Diego, CA), respectively. Antibodies against Ser15-/Ser20-phosphorylated p53 were purchased from Cell Signaling Technology (Danvers, MA). Antibody against Lys373/Lys382-acetylated p53 was purchased from Upstate%20Biotechnology">Upstate Biotechnology (Lake Placid, NY). Other reagents were from Sigma.

Plasmids—For the inducible expression of LSD1, a EcoRI-KpnI LSD1 cDNA fragment was generated from an EST clone (GenBankTM number BC048134 [GenBank] ) and cloned into pcDNA4 vector (Invitrogen, Carlsbad, CA). To generate HA-tagged LSD1, a cDNA fragment, which contains an HA epitope sequence at the 5'end and part of the LSD1 open reading frame at the 3'-end, was amplified with the forward primer (5'-AAA GGA TCC ACC ATG GGC TAC CCA TAC GAT GTT CCA GAT TAC GCT ATG TTA TCT GGG AAG-3') and the reverse primer (5'-GCT TTT CAC TAA GAA CTC GGC AG-3') and then used to replace the corresponding region in the above pcDNA4/LSD1 vector.

To generate LSD1 shRNA vector, oligonucleotides (5'-GAT CCC CGC ACC TTA TAA CAG TGA TAT TCA AGA GAT ATC ACT GTT ATA AGG TGC TTT TTG GAA A-3') and (5'-AGC TTT TCC AAA AAG CAC CTT ATA ACA GTG ATA TCT CTT GAA TAT CAC TGT TAT AAG GTG CGG G-3') were designed to target LSD1 nucleotides 862–880 (in boldface). The oligonucleotides were annealed and cloned into pTER, a polIII promoter-driven shRNA expression vector (13). The resulting plasmid was named pTER/LSD1.


Figure 1
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  		FIGURE 1.
LSD1 is required for cell proliferation. A, generation of MCF7 cell lines inducibly expressing LSD1. Levels of HA-tagged LSD1 and GAPDH were assayed in MCF7-pTR-7 and MCF7-HA-LSD1–2/-6/-22 cells cultured in the absence (–) or presence (tet) of tetracycline for 4 days. B, LSD1 overexpression has no effect on colony formation. MCF7-pTR-7 and MCF7-HA-LSD1–2/-6/-22 cells were cultured in the absence or presence of tetracycline for 13 days. C, generation of MCF7 cell lines inducibly expressing LSD1 shRNA. Levels of LSD1 and GAPDH were assayed in MCF7-pTR-7 and MCF7-LSD1-KD-11/-30/-46 cells cultured in the absence (–) or presence (tet) of tetracycline for 4 days. D, LSD1 is required for colony formation. MCF7-pTR-7 and MCF7-LSD1-KD-11/-30/-46 cells were cultured in the absence or presence of tetracycline for 13 days. E and F, quantification of the number of colonies shown in D. The percentage of colonies with a diameter < 1 mm (E) or > 1 mm (F) was calculated in three representative areas for each cell line. The average was plotted as the percentage of colonies increased or decreased by tetracycline or LSD1 knockdown. G, LSD1 deficiency induces a partial G2/M arrest. MCF7-LSD1-KD-11 cells were uninduced or induced to knockdown LSD1 for 4 days. The percentage of cells in each phase of the cell cycle was quantified by fluorescence-activated cell sorter analysis as described previously (12).

 
Cell Culture—The MCF7-pTR-7 cell line was generated previously by transfection of MCF7 cells with pcDNA6 vector that expresses a tetracycline repressor (12). To generate MCF7 cell lines inducibly expressing LSD1, MCF7-pTR-7 cells were transfected with pcDNA4/HA-LSD1 as well as a pBabe vector for puromycin selection. To generate MCF7 cell lines inducibly expressing LSD1 shRNA, MCF7-pTR-7 cells were transfected with pTER/LSD1 and the pBabe vector for puromycin selection.

Colony Formation Assay—MCF7 cells seeded at 500 per well in a 6-well plate were incubated in the absence or presence of tetracycline (1.0 µg/ml) for 10 days, followed by mock-treatment (control) or treatment with various DNA damage agents for 6 h, and then maintained for 4 days. Cells were fixed with fixative (7 parts methanol:1 part glacial acetic acid) for 10 min and then stained with crystal violet (0.2 g/liter) for 20 min.

Western Blot Analysis—Cells were washed twice with PBS, resuspended with 2x SDS sample buffer, incubated at 95 °C for 5 min, and used for Western blot analysis as described previously (14).

DNA Histogram Analysis—Cells were seeded at 2 x 105 cells per 6-cm plate in the absence or presence of tetracycline for 3 days. Cells were collected and stained with propidium iodide as previously described and examined by fluorescence-activated cell sorter (FACS calibur) (12).

Affymetrix GeneChip Assay and Northern Blot Analysis—Total RNAs was isolated from MCF7-pTR-7 and MCF7-LSD1-KD-46 cells using TRIzol reagent (Invitrogen). U133 plus GeneChip was purchased from Affymetrix (Santa Clara, CA), which contains oligonucleotides representing 37,000 unique human transcripts. GeneChip analysis was performed according to the manufacturer's instructions. Northern blot analysis and preparation of p53, p21, GAPDH, and MDM2 probes were described previously (14).

Immunoprecipitation—Cells extracts were prepared in 0.5% Non-idet P-40 lysis buffer (150 mM NaCl, 0.5% Nonidet P-40, and 50 mM Tris, pH 8.0), and p53 was immunoprecipitated with either anti-p53 (Pab421 and Pab1801), anti-Lys373/Lys382-acetylated p53, or anti-Ser15/Ser20-phosphorylated p53 overnight at 4 °C. After four washes with LBX(100) (100 mM NaCl, 20 mM Hepes, pH 7.4, 0.5% Triton X-100, and 1% protease inhibitor mixture), immunoprecipitated p53 was resuspended with 2x SDS sample buffer, incubated at 95 °C for 5 min, and used for Western blot analysis as described previously (14).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 EXPERIMENTAL PROCEDURES
 RESULTS
DISCUSSION
 REFERENCES
 
To determine whether LSD1 demethylase activity has a global impact on cell proliferation, we generated MCF7 cell lines, which inducibly express N-terminally HA-tagged LSD1 under the control of the tetracycline-regulated promoter. Three representative cell lines, MCF7-HA-LSD1–2/-6/-22, along with parental MCF7-pTR-7 cell line, are shown in Fig. 1A. The level of GAPDH was determined as a loading control. Next, we performed colony formation assay and found that LSD1 overexpression had no effect on cell proliferation (Fig. 1B). As a control, tetracycline was not found to have any effect on MCF7-pTR-7 cell proliferation (Fig. 1B, the first column).


Figure 2
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  		FIGURE 2.
LSD1 knockdown sensitizes cells to growth suppression mediated by DNA damage or Nutlin-3. MCF7-pTR-7 and MCF7-LSD1-KD-46 cells were cultured in the absence or presence of tetracycline for 10 days, followed by mock-treatment (control) or treatment with 8.6 µM doxorubicin (Dox), 10 µM camptothecin (CPT), or 20 µM Nutlin-3 for 6 h and then maintained for 4 days.

 


Figure 3
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  		FIGURE 3.
LSD1 is required for efficient p53 stabilization and transcriptional activity. A, cells extracts were prepared from MCF7-LSD1-KD-11/-30/-46 cells uninduced (–) or induced (+) to knock down LSD1 for 4 days and then untreated or treated with 0.7 µM doxorubicin for 3 or 6 h. Levels of p53, p21, and MDM2 were detected with anti-p53 (Pab421 and Pab1801), anti-p21, and anti-MDM2 (SMP14 and Ab-2) antibodies, respectively. B, Northern blots were prepared using 15 µg of total RNAs isolated from MCF7-pTR-7 and MCF7-LSD1-KD-46 cells treated as in A. The blots were probed with cDNAs derived from p53, p21, GAPDH, and MDM2, respectively. C and D, LSD1 has no effect on the level of Lys373/Lys382-acetylated p53 and Ser15-/Ser20-phosphorylated p53. Cells extracts were prepared from MCF7-LSD1-KD-46 cells uninduced (–) or induced (+) to knockdown LSD1 for 4 days and then untreated or treated with 0.7 µM doxorubicin for 8 h. p53 was immunoprecipitated with either anti-p53 (Pab421 and Pab1801), anti-Lys373/Lys382-acetylated p53, or anti-Ser15-/Ser20-phosphorylated p53 antibodies and quantified by Western blot analysis.

 
To determine whether LSD1 deficiency has an effect on cell proliferation, we generated three MCF7 cell lines, MCF7-LSD1-KD-11/-30/-46, in which LSD1 is inducibly knocked down by the tetracycline-inducible shRNA expression system. For each cell line, LSD1 levels were significantly decreased upon induction of LSD1 shRNA for 4 days (Fig. 1C). Next, we performed a 6-day growth curve on MCF7-pTR-7 and MCF7-LSD1-KD-30 cells and found that there was a decrease in the number of proliferating cells after knockdown of LSD1 for 6 days (data not shown). To further address the long term effect of LSD1 knockdown on cell proliferation, colony formation assay was done (Fig. 1D). We found that the ability of MCF7 cells to proliferate was attenuated upon knockdown of LSD1 for 10 days. Thus, we further characterized this and found that the total number of colonies was not affected by tetracycline. However, the number of small colonies (less than 1 mm in diameter) was significantly increased by LSD1 knockdown in MCF7-LSD1-KD-11/-30/-46 cells compared with that by tetracycline in parental MCF7-pTR-7 cells (Fig. 1E). Concomitantly, there was a significant decrease in the number of large colonies (more than 1 mm in diameter) in all three LSD1 knockdown cell lines (Fig. 1F). Together, these results suggest that LSD1 is required for normal cell proliferation. To further characterize the cell cycle profile of LSD1 knockdown cells, DNA histogram assay was performed with MCF7-LSD1-KD-11 cells induced to express LSD1 shRNA for 4 days. We found that upon LSD1 knockdown, the number of cells in G1 was decreased, concomitantly with an increase in the number of cells in G2/M (Fig. 1F). These data indicate that LSD1 is required for cell cycle progression.

To investigate whether LSD1 modulates p53 function, MCF7-pTR-7 and MCF7-LSD1-KD-46 cells were pretreated with tetracycline to knockdown LSD1 for 10 days, followed by treatment with a DNA damage agent (doxorubicin or camptothecin) or Nutlin-3 for 6 h, and then maintained for 4 days. Nutlin-3 is an MDM2 inhibitor, which activates p53 without causing DNA damage (15). We showed that in MCF7 cells, growth suppression induced by DNA damage or Nutlin-3 was markedly increased by LSD1 knockdown but not treatment with tetracycline (Fig. 2).

To further characterize the prosurvival function of LSD1, Western blot analysis was performed to measure the levels of p53 and its target gene products, p21 and MDM2. Thus, MCF7-LSD1-KD-11/-30/-46 cells were uninduced or induced to knock down LSD1 for 4 days, followed by treatment with doxorubicin for 3 or 6 h (Fig. 3A). For each cell line, a marked decrease in LSD1 was detected upon induction of LSD1 shRNA and endogenous p53 was activated upon treatment with doxorubicin, which led to induction of p21 and MDM2 (Fig. 3A). Interestingly, we found that LSD1 knockdown decreased to some extend p53 stabilization in the first 3 h following treatment with doxorubicin, resulting in a decrease in p21 and MDM2 induction (Fig. 3A, compare lanes 3, 9, and 15 with lanes 4, 10, and 16, respectively). However, the long term stabilization of p53 induced by DNA damage was not affected by LSD1 knockdown (Fig. 3A, doxorubicin treatment for 6 h, compare lanes 5, 11, and 17 with lanes 6, 12, and 18, respectively; treatment with doxorubicin for 12 h, data not shown).

Next, Northern blot analysis was performed to examine whether the levels of p53, p21, and MDM2 transcripts are affected by LSD1 knockdown. MCF7-pTR-7 and MCF7-LSD1-KD-46 cells were pretreated with tetracycline for 4 days, followed by doxorubicin treatment for 3 or 6 h. We found that in MCF7-pTR-7 cells, there was no change in the level of p53 transcript (Fig. 3B). As expected, p21 and MDM2 were induced upon treatment with doxorubicin regardless of tetracycline pretreatment (Fig. 3B, compare lanes 1, 3, and 5 with lanes 2, 4, and 6, respectively). We also found that in MCF7-LSD1-KD-46 cells, LSD1 knockdown had no effect on p53 expression (Fig. 3B, compare lanes 7 and 8). Interestingly, LSD1 knockdown significantly decreased the induction of MDM2 and, to a lesser extent, p21 following treatment with doxorubicin for 3 h (Fig. 3B, compare lanes 9 and 10). However, the long term induction of p21 and MDM2 by DNA damage was not affected by LSD1 knockdown (Fig. 3B, treatment with doxorubicin for 6 h, compare lanes 11 and 12). Thus, the effect of LSD1 knockdown on p21 and MDM2 transcription is likely responsible for the decreased expression of p21 and MDM2 proteins via decreased stabilization of p53 protein.

Since LSD1 is a demethylase, we determined whether LSD1 has any effect on p53 methylation. MCF-7-LSD1-KD-46 cells were uninduced or induced to knock down LSD1 for 4 days, followed by treatment with doxorubicin for 8 h. Using commercially available antibodies against methylated p53 or antibodies against methylated lysines, the methylation status of p53 was not found to be altered by LSD1 knockdown (data not shown). Since p53 methylation appears to affect its acetylation and phosphorylation, specific antibodies against acetylated or phosphorylated p53 were used to examine those modifications. As shown in Fig. 3C, LSD1 levels were decreased upon knockdown and p53 was stabilized by doxorubicin. Interestingly, we found that LSD1 knockdown had no significant effect on the levels of total p53, Lys373/Lys382-acetylated p53, and Ser15-/Ser20-phosphorylated p53 induced by DNA damage (Fig. 3D). Taken together, our data suggest that the pro-survival effect of LSD1 is mediated at least in part through the regulation of p53 stability and transcriptional activity.

To further address the pro-survival function of LSD1, we wanted to determine which genes are specifically regulated upon LSD1 knockdown. Thus, we performed Affymetrix GeneChip analysis using MCF7-LSD1-KD-46 cells uninduced or induced to knock down LSD1 for 4 days. Several novel LSD1 target genes, such as S100A8, which encodes a calcium-binding protein, and DEK, a proto-oncogene, were found to be repressed upon LSD1 knockdown (Table 1). Furthermore, their repression upon LSD1 knockdown was confirmed by Northern blot analysis (Fig. 4, compare lanes 1, 3, and 5 with lanes 2, 4, and 6, respectively). Therefore, it is likely that S100A8, DEK, and other LSD1 target genes play a role in LSD1 pro-survival function.


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  		TABLE 1
Genes regulated by LSD1

 


Figure 4
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  		FIGURE 4.
LSD1 regulates S100A8 and DEK expression. Northern blots were prepared using 15 µg of total RNAs isolated from MCF7-LSD1-KD-46 cells uninduced (–) or induced (+) to knockdown LSD1 for 4 days and then untreated or treated with doxorubicin for 3 or 6 h. The blots were probed with cDNAs derived from DEK, S100A8, and GAPDH genes, respectively.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 EXPERIMENTAL PROCEDURES
 RESULTS
 DISCUSSION
REFERENCES
 
LSD1 is known to play a role in REST-dependent repression of neural-specific genes and activation of androgen receptor-dependent genes via chromatin remodeling (4, 7). However, the precise physiological significance of LSD1 is yet unclear. Here, we found, for the first time, that LSD1 is required for cell proliferation. We also found that LSD1 knockdown induces a partial G2/M arrest. Furthermore, we found that LSD1 may exert its pro-survival function by modulating the p53-dependent DNA damage response. In particular, LSD1 is necessary for the rapid stabilization of p53 in response to DNA damage leading to prompt induction of p21 and MDM2, both of which are key players in the p53 pro-survival pathway (16). We speculate that a rapid initial activation of p53 is crucial to induce pro-survival mechanisms, such as cell cycle arrest and DNA repair, to limit the extent of damage to DNA. Consistent with this, a recent study identified LSD1 as a novel biomarker predictive for prostate cancer with aggressive biology (17).

Post-translational modifications of p53 play an important role in regulating p53 stability and transcriptional activity in response to DNA damage (18). Among those, acetylation of p53 at specific C-terminal lysine residues by acetyltransferases, such as p300/CBP (Lys372/Lys382) and P/CAF (Lys320), differentially regulates the expression of target genes involved in cell cycle arrest, apoptosis, cell proliferation, or senescence (19). Indeed, recent studies showed that altered acetylation in various p53 mutants effects the affinity of p53 for downstream target promoters and the ability of p53 to recruit diverse co-factors, for instance p300, Brg1, HDAC1, or SIRT1, to initiate or prevent gene transcription (20). In addition, acetylated lysine residues in p53 are subjected to deacetylation by histone deacetylases and subsequent ubiquitination by MDM2, which leads to decreased p53 stability. Furthermore, lysine methylation of p53 was recently reported to modulate p53 stability and transcriptional activity in both positive and negative manners, depending on the methylation site (9, 11). Therefore, we speculate that the modification status of a particular lysine residue is a determinant in mediating specific gene expression profile to trigger appropriate p53 tumor suppressive function. Although we were unable to detect any alteration in methylated or acetylated p53, it remains possible that one or more lysine residues are regulated by LSD1 demethylase activity. It is also possible that the effect of LSD1 on p53 transcriptional activity is mediated through demethylation of MDM2 or other modifiers of p53.

In this study, we identified, for the first time, various genes specifically regulated by LSD1, such as DEK, S100A8, PLCL1, and ADAMTS1 (Table 1). DEK, a nuclear DNA-binding protein, is frequently overexpressed in many types of cancers and its expression correlates with cell proliferation (21). In addition, DEK is found to be expressed as DEK-CAN fusion protein, which may be responsible for a subset of patients with acute myeloid leukemia (22). Although DEK has been implicated in transcriptional regulation and chromatin remodeling, its precise physiological role remains to be elucidated (23). Nevertheless, DEK and other LSD1 target genes are likely to mediate the pro-survival function of LSD1.


   FOOTNOTES
 
* This work was supported by National Institutes of Health Grants CA076069, CA081237, and CA102188. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Back

1 To whom correspondence should be addressed: Center for Comparative Oncology, 2128 Tupper Hall, Davis, CA 95616. Tel.: 530-754-8404; Fax: 530-752-6042; E-mail: xbchen{at}ucdavis.edu.

2 The abbreviations used are: LSD1, lysine-specific demethylase 1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HA, hemagglutinin. Back


   ACKNOWLEDGMENTS
 
We thank Anita Chen for technical assistance and the members of the Chen laboratory for helpful discussions.



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 ABSTRACT
 INTRODUCTION
 EXPERIMENTAL PROCEDURES
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 DISCUSSION
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Copyright © 2007 by the American Society for Biochemistry and Molecular Biology.