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Genes Dev. May 15, 2009; 23(10): 1171–1176.
PMCID: PMC2685535

The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A–ARF locus in response to oncogene- and stress-induced senescence


The tumor suppressor proteins p16INK4A and p14ARF, encoded by the INK4A–ARF locus, are key regulators of cellular senescence. The locus is epigenetically silenced by the repressive H3K27me3 mark in normally growing cells, but becomes activated in response to oncogenic stress. Here, we show that expression of the histone H3 Lys 27 (H3K27) demethylase JMJD3 is induced upon activation of the RAS–RAF signaling pathway. JMJD3 is recruited to the INK4A–ARF locus and contributes to the transcriptional activation of p16INK4A in human diploid fibroblasts. Additionally, inhibition of Jmjd3 expression in mouse embryonic fibroblasts results in suppression of p16Ink4a and p19Arf expression and in their immortalization.

Keywords: Cancer, senescence, INK4A, ARF, histone methylation, histone demethylation

Senescence induced by oncogenes and other stress signals has been identified as a fail-safe program that counters malignant transformation (Serrano and Blasco 2007; Prieur and Peeper 2008). The tumor suppressor proteins p16INK4A and p14ARF are key regulators of senescence and the expression of these proteins leads to a G1 arrest of the cell cycle (Gil and Peters 2006). p16INK4A causes this arrest by working as a CDK4/CDK6 inhibitor acting upstream of the pRB–E2F pathway, whereas p14ARF (p19Arf in mice) controls the level of p53 by inhibiting the p53-specific ubiquitin ligase MDM2 (Gil and Peters 2006). In actively growing human diploid fibroblasts, the INK4A–ARF locus is silenced by histone H3 Lys 27 trimethylation (H3K27me3) imposed by the Polycomb Group (PcG) proteins. When such cells are exposed to cellular stress, the H3K27me3 mark on the locus is decreased, resulting in expression of both p16INK4A and p14/p19ARF (Jacobs et al. 1999; Bracken et al. 2007; Kotake et al. 2007). In contrast, aberrant expression of PcG proteins leads to increased H3K27me3 levels and silencing of the INK4A–ARF locus. The PcG proteins are frequently overexpressed in human tumors, and their contribution to proliferation is ascribed primarily to their role in regulating the expression of the INK4A–ARF locus (Jacobs et al. 1999; Bracken et al. 2007; Dietrich et al. 2007).

Recently, we and others identified two histone lysine demethylases—JMJD3 and UTX—that specifically catalyze the demethylation of di- and trimethylated H3K27 (H3K27me2/me3) (Agger et al. 2007; De Santa et al. 2007; Jepsen et al. 2007; Lan et al. 2007; Lee et al. 2007). We wanted to understand whether one or both of these enzymes could be involved in the active removal of H3K27me3 from the INK4A–ARF locus during induction of stress-induced senescence and oncogene-induced senescence (OIS).

Results and Discussion

JMJD3 expression is induced by activation of the RAS–RAF pathway

To investigate a potential role of JMJD3 and UTX in OIS, we generated TIG3–hTERT human diploid fibroblasts expressing a conditional form of the constitutively activated BRAF oncogene. This version of BRAF is fused to the ligand-binding domain of the estrogen receptor (ER), and the activity of this protein is rapidly induced by 4-hydroxytamoxifen (OHT) (Woods et al. 1997). These cells, TIG3 BRAF-ER, rapidly undergo OIS upon BRAF activation, concomitant with an increased expression of p16INK4A (Fig. 1A,E). To understand whether JMJD3 and/or UTX would be differentially expressed when cells enter OIS, we measured the expression levels of JMJD3 and UTX in response to BRAF activation by real-time quantitative PCR (qPCR) and Western blotting. As shown in Figure 1, B and E, the activation of BRAF leads to a significant increase in JMJD3 expression levels, whereas no change was observed in UTX expression.

Figure 1.
JMJD3 expression is induced by oncogenic BRAF and HRASV12. (A–C) Expression levels of p16INK4A and p14ARF (A), JMJD3 and UTX (B), and EZH2 and SUZ12 (C) in TIG3 BRAF-ER at different times following OHT treatment determined by RT-qPCR. Data presented ...

If JMJD3 is required for the initial removal of the H3K27me3 mark before p16INK4A expression, one would expect that the increase in JMJD3 expression would occur prior to the increase in p16INK4A expression. As shown in Figure 1, B and E, increased JMJD3 expression is already observed 2–4 h after activation of BRAF, whereas p16INK4A expression is not significantly increased before 24–48 h. In agreement with this, an increase in JMJD3 protein levels is already apparent 6 h after OHT treatment, whereas the increase in p16INK4A protein is first noticeable after 24 h (Fig. 1E). Similar effects were obtained when we expressed BRAF-ER in BJ cells immortalized by hTERT (Fig. 1D).

Consistent with previous reports (e.g., see Bracken et al. 2007), levels of EZH2 and SUZ12, two subunits of the H3K27 methyltransferase complex PRC2, also decrease following the activation of BRAF (Fig. 1C,E). The decrease in EZH2 levels occurred later than the increase in JMJD3 expression, suggesting that JMJD3 may be affecting the transcription of the INK4A–ARF locus prior to the decrease of the PRC2 complex associated with the locus. From these data we conclude that JMJD3 expression is induced rapidly in response to BRAF activation and that this induction occurs before induction of INK4A transcription. This indicates that JMJD3 could be involved in the initial demethylation of the INK4A–ARF locus in response to oncogenic stress.

To understand if other oncogenes, known to induce senescence, would induce the expression of JMJD3 prior to the activation of the INK4A–ARF locus, we monitored the effect of oncogenic HRASV12. As demonstrated in Figure 1F, ectopic expression of HRASV12 led to the activation of JMJD3 and p16INK4A. A similar effect was also observed on INK4A, but not on ARF, expression in BJ-hTERT cells infected with a HRASV12-expressing virus (Fig. 1G). These results suggest that hyperactivation of the RAS–RAF pathway leads to the activation of the INK4A gene in human cells through the transcriptional induction of JMJD3, whereas the activation of ARF is only observed by BRAF.

We also investigated if other types of stress associated with senescence can induce the expression of JMJD3, and as shown in Figure 1H, UV-irradiation of TIG3 human diploid fibroblasts led to a significant increase in JMJD3 protein levels. Taken together with the results reported above, this suggests that JMJD3 expression is increased in response to several types of stress.

JMJD3 contributes to the induction of p16INK4A expression in response to BRAF

Having established that JMJD3 is induced in response to oncogenic stress, we were interested in understanding the molecular mechanisms leading to JMJD3 activation. Previously, the transcription factor NF-κB has been implicated in the transcriptional activation of JMJD3 during inflammatory responses (De Santa et al. 2007). We speculated whether NF-κB also could be involved in the induction of JMJD3 after oncogene stimulation. To investigate this, we tested whether the IkBα-SR “superrepressor,” a strong inhibitor of NF-κB signaling (Jobin et al. 1998), affected JMJD3 induction in response to BRAF. IkBα-SR did not change the transcriptional activation of JMJD3 in response to BRAF (data not shown), indicating that NF-κB is not involved in the transcriptional activation of JMJD3 regulation in response to oncogene stimulation.

To gain mechanistic insight into how JMJD3 is induced in response to oncogenic stress, we cloned the human JMJD3 promoter and established a reporter assay in U2OS cells expressing BRAF-ER. The JMJD3 promoter features two transcriptional start sites (TSSs) (Fig. 2B); one of which is used in embryonic stem (ES) cells (ESC-TSS), and another that is used in macrophages (MF-TSS) (De Santa et al. 2007). In response to BRAF activation, a promoter construct, P1, containing 3422 base pairs (bp) immediately upstream of the MF-TSS, is induced to a significantly higher level than the JMJD3 reporter construct P8, containing 2928 bp upstream of the ESC-TSS start site (Fig. 2A,B). Reporter constructs P2, P3, P4, and P5, containing 2439, 2314, 2224, and 2173 bp immediately upstream of the MF-TSS, respectively, were also induced. The induction was lost in constructs P6 and P7 (spanning 2102 and 1428 bp upstream of the MF-TSS, respectively) indicating that the motifs crucial for BRAF induction of the JMJD3 promoter are found between 2102 and 2173 bp upstream of the MF-TSS (Fig. 2B). This region of the promoter contains consensus sites for the following transcription factors: RAP1, Sp1, Krox-20, ETF, C/EBPα, and AP-1. Notably, AP-1 is activated by the extracellular signal-regulated kinase (ERK), which regulates cell proliferation and is a component of the RAS–RAF–MEK–ERK kinase pathway. Hence, the AP-1 transcription factors are good candidates for acting as transactivators of JMJD3 transcription in response to RAS–RAF–MEK–ERK signaling.

Figure 2.
Induction of p16INK4A expression in response to BRAF is regulated by JMJD3. (A) Reporter assays using lysates from BRAF-ER U2OS cells transfected with various human JMJD3 promoter/luciferase reporter gene constructs with or without OHT stimulation. OHT ...

Since the increase in JMJD3 expression precedes the induction of p16INK4A during BRAF-induced senescence, we wanted to understand if the increase in p16INK4A expression was dependent on JMJD3. For this purpose, we generated two different lentiviral shRNA constructs encoding shRNAs that targeted JMJD3 expression (Supplemental Fig. S1A). We infected TIG3 BRAF-ER cells with these constructs as well as with a control shRNA construct selected for stable genomic integration, and measured the mRNA and protein levels of p16INK4A and JMJD3 before and after BRAF induction. As shown in Figure 2, C and G, and Supplemental Figure S1A, both shRNAs to JMJD3 inhibited the expression of JMJD3. Importantly, this inhibition strongly reduced the induction of p16INK4A expression following activation of BRAF (Fig. 2D,G; Supplemental Fig. S1B,C). Interestingly, JMJD3 depletion also appeared to increase EZH2 levels, perhaps reflecting an increased proliferative activity in JMJD3 knockdown cells. No change in UTX expression levels was observed (Fig. 2E–G). Thus, from these data we conclude that JMJD3 contributes significantly to the transcriptional activation of the INK4A–ARF locus. This is most likely a consequence of a lack of H3K27me3 demethylation at the locus resulting in transcriptional repression. However, consistent with the increased levels of p16INK4A expression after sustained activation of B-RAF, even in the presence of an shRNA to JMJD3, down-regulation of JMJD3 was not sufficient to prevent OIS (data not shown).

Ectopic expression of JMJD3 results in the activation of the INK4A–ARF locus and the inhibition of cell proliferation

Next, having established that induction of p16INK4A is dependent on JMJD3, we speculated whether ectopic expression of JMJD3 alone would be sufficient to induce transcription from the INK4A–ARF locus. Since we were not able to efficiently express full-length JMJD3 by retroviral transduction, we expressed a catalytically active fragment of JMJD3 (JMJD3s) in mouse embryo fibroblasts (MEFs). We transduced a panel of different primary MEFs, which were either wild type or carried mutations in genes involved in stress-induced senescence: Tp53−/−, Arf−/−, or Ink4a-Arf−/−, with viruses expressing JMJD3s or a catalytically inactive fragment of JMJD3s, JMJD3sMT. After transduction and 3 d of puromycin selection the expression levels of Ink4a and Arf were measured by RT–qPCR. As shown in Figure 3A, ectopic expression of JMJD3s led to increased levels of Ink4a, but not Arf, in wild-type, Tp53−/−, and Arf−/− MEFs. Since this effect was strictly dependent on the catalytic activity of Jmjd3 (Fig. 3A), these results suggest that Jmjd3 can activate Ink4a expression by demethylating H3K27me3 associated with the locus. Similarly, we found that the activation of INK4A in human diploid fibroblasts was dependent on the catalytic activity of JMJD3 (Fig. 3B).

Figure 3.
Overexpression of JMJD3 results in increased expression of INK4A in MEFs and TIG3 cells. (A) Wild-type, Tp53−/−, Arf−/−, and Ink4a–Arf−/− cells were infected with pBabe constructs expressing a HA-tagged ...

To investigate the consequence of increased JMJD3 activity, we measured the proliferation of different infected pools of MEFs (Fig. 3C). Expression of JMJD3s, but not of JMJD3sMT, strongly inhibited the proliferation of wild-type and Arf−/− cells, again underscoring the importance of the demethylase activity of JMJD3 for its biological activity. Ectopic expression of JMJD3s, although expressed at much higher levels than in wild-type MEFs (Supplemental Fig. S2C), did not affect the proliferation of Tp53−/− or Ink4a–Arf−/− MEFs (Fig. 3C). Taken together, these results demonstrate that JMJD3\ can induce the expression of p16Ink4a leading, to a strong inhibition of cell proliferation.

Down-regulation of Jmjd3 leads to immortalization of primary MEFs

MEFs undergo stress-induced senescence after five to six passages, when grown in atmospheric O2 (20%) under a 3T3 protocol. The stress response is a consequence of the high oxygen levels that inflict oxidative damage to the cells resulting in senescence (Parrinello et al. 2003). The induction of senescence is dependent on a functional Ink4a–Arf locus, although it is the p19Arf protein that mediates the response in mouse cells. Thus, inactivation of Arf is sufficient to overcome the stress-induced senescence process in MEFs (Kamijo et al. 1997). However, since the expression of the Ink4a and Arf genes is epigenetically coregulated (Bracken et al. 2007), we investigated the functional relevance of Jmjd3 for the regulation of the entire Ink4a–Arf locus in MEFs.

To do this, we infected MEFs with a lentiviral construct that efficiently inhibited the expression of Jmjd3 (Supplemental Fig. S3A). The cells were subsequently subjected to a 3T3 protocol and samples were harvested for protein preparations at the indicated times (Fig. 4A,B). As demonstrated in Figure 4 and Supplemental Figure S3B, depletion of Jmjd3 results in impaired expression of both p16Ink4a and p19Arf and a rescue of the senescence normally observed around passage 5–6.

Figure 4.
shRNA-mediated depletion of Jmjd3 inhibits stress-induced expression of p16Ink4a and p19Arf and leads to immortalization of primary MEFs. Primary MEFs were transduced with shRNA plasmids targeting Jmjd3 [shJmjd3(2837)] or control shRNA. (A) Jmjd3 depletion ...

As in human fibroblasts, MEFs also undergo OIS in response to activated oncogenes such as RasV12. To understand if Jmjd3 in mice has similar functions in OIS we transduced primary MEFs with lentiviruses expressing shJmjd3 and RasV12 as indicated in Figure 4, C and D. After selection, the expression levels of Ink4a and Arf were measured by RT–qPCR and immunoblotting. As demonstrated in Figure 4, C and D, depletion of Jmjd3 results in impaired expression of Ink4a, as well as Arf, suggesting that mouse Jmjd3, as human JMJD3, contributes to the activation of the Ink4a–Arf locus during OIS.

JMJD3 associates with the INK4A–ARF locus

Previous results have suggested that JMJD3 acts as a transcriptional coactivator by removing H3K27me3 at target genes (Agger et al. 2007; De Santa et al. 2007; Jepsen et al. 2007; Lan et al. 2007; Lee et al. 2007). Consequently, JMJD3 may contribute to the regulation of p16INK4A and p14/p19Arf expression by demethylating the INK4A–ARF locus. Previously, we mapped the binding of the PcG proteins and H3K27 trimethylation throughout the INK4A–ARF locus in human diploid fibroblasts, primary MEFs, and in cell populations enriched for hematopoietic stem cells (Bracken et al. 2007). The results from these studies showed that H3K27me3 is associated primarily with the INK4A, and not the ARF, locus in the explanted fibroblasts. To understand if JMJD3 is associated with the INK4A–ARF locus in TIG3 BRAF-ER cells, we performed chromatin immunoprecipitation (ChIP) experiments followed by real-time qPCR (qChIP) using an antibody specific for JMJD3. As shown in Figure 5, A and C, the activation of BRAF leads to an increased binding of JMJD3 to regions just upstream of the TSS for INK4A. Moreover, the increased binding correlates with a decrease in H3K27me3 levels bound at the INK4A–ARF locus (Fig. 5B) and the decrease of the PcG protein CBX8 (Fig. 5C), a component of the Polycomb-Repressive Complex 1 that is required for the repression of the INK4A–ARF locus (Dietrich et al. 2007). These results show that JMJD3 directly binds to the INK4A–ARF locus and suggests that it contributes to the transcriptional induction of the locus by demethylating H3K27me3. If JMJD3 is responsible for the initial removal of H3K27me3 on the INK4A–ARF locus in response to activation of the RAS–RAF pathway, the H3K27me3 levels would be affected by JMJD3 depletion. We performed ChIP experiments using TIG3-BRAF-ER cells and MEFs depleted for JMJD3 and expressing RasV12. The amount H3K27me3 relative to total H3 at the INK4A locus was measured. As shown in Figure 5, D and E, depletion of JMJD3 impairs the H3K27me3 reduction observed in response to oncogene activation.

Figure 5.
JMJD3 associates with the INK4A–ARF locus. (A) Schematic presentation of the INK4A–ARF locus with an indication of the primer pairs (PP) used in B–D. (B,C) ChIP assays using lysates from TIG3 BRAF-ER cells treated with or without ...

JMJD3 expression is significantly decreased in several types of primary tumors

To obtain insight into whether deregulation of JMJD3 might have a role in cancer, we searched the Oncomine database (http://www.oncomine.org) for differential JMJD3 expression in normal versus tumor tissue. Notably, the expression of JMJD3 was significantly reduced relative to normal tissues in various cancers, including lung and liver carcinomas, as well as various hematopoietic malignancies (Fig. 5F; Supplemental Fig. S4). The most dramatic decrease of JMJD3 transcription was noted in a subset of lymphomas and leukemias. Thus, JMJD3 expression levels were reduced more than two standard deviations below the mean when compared with normal B (NB) cells in 64% (44 out of 69) of diffuse large B-cell lymphoma (DLBL) samples, in 62% (19 out of 31) of Burkitt lymphomas (BL), in 50% (eight out of 16) of hairy cell leukemias (HCL), and in all (four out of four) multiple myelomas (MM). In contrast, follicular lymphomas (FL), mantle cell lymphomas (MCL), and B-cell chronic lymphocytic leukemias (B-CLL) featured JMJD3 levels above or in the range of NB cells (Fig. 5F). These results suggest that decreased expression of JMJD3 might contribute to the development of some human cancers, most likely by reducing H3K27 demethylation of the INK4A–ARF tumor suppressor locus.

The INK4A–ARF locus is frequently lost in human cancers (Sherr 2001). The locus encodes two distinct tumor suppressor proteins: p16INK4A and p14ARF (Quelle et al. 1997; Sherr 2001). p16INK4A and p14ARF/p19ARF fulfill important roles in regulating the cell cycle and in the integration of stress pathways and cellular fates (Quelle et al. 1997; Sherr 2001). Thus, the p16INK4A protein inhibits cell cycle progression through repression of the CDK4/6 cyclin complexes and by preventing the phosphorylation of pRB, whereas the p14ARF and p19ARF proteins play important roles in regulation of the p53 pathway (Serrano et al. 1996; Kamijo et al. 1997).

In the present study, we showed that JMJD3 contributes to the normal activation of the INK4A–ARF tumor suppressor locus in response to stressful stimuli, advancing JMJD3 as a potential tumor suppressor gene. In agreement with this, we found that ectopic expression of JMJD3 leads to increased levels of p16INK4A and senescence (Fig. 3; data not shown).

A key question is whether JMJD3 is mutated, deleted, or otherwise silenced/inactivated in cancers. As mentioned above, data mining indicates that JMJD3 is decreased significantly in subsets of cancers (Fig. 5F). Moreover, as noted previously (Cloos et al. 2008), the JMJD3 gene is located on chromosome 17 in close vicinity to the TP53 (p53) tumor suppressor gene. Allele loss at chromosome 17p, where both TP53 and JMJD3 are found, constitutes a common genetic lesion observed in a variety of human cancers (Nigro et al. 1989). Interestingly, it has been proposed that this genomic area may include another tumor suppressor gene in addition to TP53, since allelic losses at this genomic position are rather poorly correlated with mutations in TP53. Thus, JMJD3 seems to be a strong candidate for this “additional” tumor suppressor gene. Indeed, loss of both TP53 and JMJD3 may be expected to inactivate both the pRB and p53 tumor suppressor pathways.

Another question that remains to be answered is what mechanisms lead to the transcriptional induction and recruitment of JMJD3 to the INK4A–ARF locus in response to oncogenic stress. The RAS/RAF/MEK/ERK pathway controls transcriptional programs, which can lead to different cellular outcomes such as apoptosis, transformation, cell proliferation, or senescence. Activated ERK, the downstream kinase in this pathway, can enter the nucleus and phosphorylate transcription factors such as c-JUN and c-FOS. These downstream transcription factors could regulate JMJD3. Indeed, the minimal promoter area necessary for JMJD3 induction in response to BRAF features a binding site for AP-1, a target of the ERK kinases.

The transcription factor AP-1 is formed as a dimer between members of the JUN family and members of the FOS or ATF families, and has been implicated in the control of transcription from the INK4A–ARF locus. Thus, c-JUN and FRA-1 proteins have been identified as major effectors of RAS-mediated transformation (Mechta et al. 1997). Similarly, AP-1 has been shown to play important roles in RAS-induced cellular transformation (Johnson et al. 1996). Finally, AP-1 heterodimers have been shown to cooperate with RAS to activate the ARF promoter (Ameyar-Zazoua et al. 2005). We therefore suggest a model (Fig. 5G) in which the ERK kinase acts to induce JMJD3 through a transcription factor, probably AP-1. In turn, JMJD3 demethylates H3K27 at the INK4A–ARF locus to induce expression of p16INK4A and p14ARF/p19ARF, thus fulfilling an important tumor suppressor function.

Materials and methods

Data mining and statistical analysis

Microarray data from Oncomine Web site (http://www.oncomine.org) were compared between groups using the Mann-Whitney U-test (two-tailed). For all tests, P ≤ 0.05 was considered significant.

ShRNA constructs

The following shRNA constructs against mouse Jmjd3 were in the LKO.1-puro vector from Sigma: shJmjd3(5876), TRCN0000095264; and shJmjd3(2837), TRCN0000095265. ShRNA constructs against human JMJD3 were cloned in the flap-Hygro vector targeting the following sequences: shJMJD3(3302), GGCGACAGAAGGAGCATCA; and shJMJD3(4705), GATGATCTCTATGCATCCA.

Generation of antibodies to JMJD3

The JMJD3 antibody was generated in rabbits, using affinity-purified GST-JMJD3 (amino acids 798–1095). The antisera were affinity-purified on GST-JMJD3.

Other antibodies

Anti-H3 (ab1791, Abcam); anti-H3K27me3 (#9733, Cell Signaling); anti-Vinculin (V9131, Sigma); anti-RasV12 (Sc-520, Santa Cruz Biotechnologies); anti-CBX8 (Bracken et al. 2007); anti-EZH2 (BD43) (Bracken et al. 2007); anti-HA (MMS-101P, Covance); anti-INK4A (DCS50); anti-Ink4a (Santa Cruz Biotechnologies).

Generation of BRAF-ER TIG3 cells and MEFs

Generation of BRAF-ER TIG3 cells and MEFs is described in the Supplemental Material.

ChIP and real-time qPCR

ChIP and real-time qPCR were done essentially as described in Bracken et al. (2007). Primers used are described in the Supplemental Material.

Cloning of the JMJD3 promoter, reporter assays, and analysis of potential transcription factor-binding sites

Cloning of the JMJD3 promoter, reporter assays, and analysis of potential transcription factor-binding sites isdescribed in the Supplemental Material.


We thank members of the Helin laboratory for technical advice and fruitful discussions. We thank Jesus Gil and Gordon Peters for communicating results prior to submission. This work was supported by grants from the Novo Nordisk Foundation, the Association for International Cancer Research, the Danish Cancer Society, the Danish Medical Research Council, the Danish Natural Science Research Council, the Benzon Foundation, the Lundbeck foundation, Harboefonden, and the Danish National Research Foundation.


Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.510809.

Supplemental material is available at http://www.genesdev.org.


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