The histone demethylase enzyme KDM3A is a key estrogen receptor regulator in breast cancer

Wade, Mark; Jones, Dominic; Wilson, Laura; Stockley, Jacqueline; Coffey, Kelly; Robson, Craig; Gaughan, Luke

doi:10.1093/nar/gku1298

Cited by 89 publications

(88 citation statements)

References 57 publications

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“…It has also been reported that in solid tumors (such as breast cancer and rectal cancer), high KDM3A expression is associated with a poor prognosis. 27,28 As described earlier, KDM3A serves as an oncogenic factor in hypoxia-subjected tumors. Although KDM3A is known to be induced by hypoxia in a variety of cancers, no association has been reported between hypoxia and KDM3A in MM.…”

Section: Discussionmentioning

confidence: 89%

“…Furthermore, we investigated whether any stimulation from the microenvironment other than hypoxia affects the H3K9 demethylase Figure 4C-D). Although it has been reported that KDM3A, an H3K9 demethylase containing a jumonji domain, plays an important oncogenic role in cancer, [27][28][29] the exact role of KDM3A in the hypoxic stress response of myeloma has not been reported. We therefore sought to investigate the role of KDM3A in hypoxia.…”

Section: Upregulation Of H3k9 Demethylase Kdm3a Is Regulated By Hif-1mentioning

confidence: 99%

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Hypoxia-inducible KDM3A addiction in multiple myeloma

et al. 2018

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Key Points• Under hypoxia, KDM3A, but not IRF4, leads myeloma cells to acquire an antiapoptotic phenotype.• KDM3A regulates a long noncoding RNA, MALAT1, leading to upregulation of glycolytic genes under hypoxia.In multiple myeloma (MM), the bone marrow (BM) microenvironment may contain a myeloma cell fraction that has acquired treatment resistance by undergoing an epigenetic gene expression change. Hypoxic stress is an important factor in the BM microenvironment.Recently, we demonstrated that miR-210 was upregulated in hypoxia and downregulated IRF4, which is known as an essential factor in myeloma oncogenesis in normoxia. In the study, we demonstrated that myeloma cells still showed a strong antiapoptotic phenotype despite IRF4 downregulation, suggesting that another antiapoptotic factor might be involved under hypoxic stress. To determine the factor or factors, we conducted gene expression analysis on myeloma cells (primary samples and cell lines) that were exposed to chronic hypoxia and observed upregulation of glycolytic genes and genes encoding H3K9 demethylases in myeloma cells with hypoxia. Among these, KDM3A was most significantly upregulated in all examined cells, and its knockdown induced apoptosis of myeloma cells in chronic hypoxia.Expression of KDM3A was dependent on HIF-1a, which is a transcription factor specifically upregulated in hypoxia. We further demonstrated that an essential target of KDM3A was a noncoding gene, MALAT1, whose upregulation contributed to acquisition of an antiapoptotic phenotype by accumulation of HIF-1a, leading to upregulation of glycolytic genes under hypoxia. This process was independent from IRF4. These results led us to conclude that the hypoxia-inducible HIF-1a-KDM3A-MALAT1 axis also contributes to acquisition of the antiapoptotic phenotype via upregulation of glycolysis-promoting genes. Thus, this axis is a promising therapeutic target against myeloma cells in the BM microenvironment.

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Section: Discussionmentioning

confidence: 89%

Section: Upregulation Of H3k9 Demethylase Kdm3a Is Regulated By Hif-1mentioning

confidence: 99%

Hypoxia-inducible KDM3A addiction in multiple myeloma

et al. 2018

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“…For example, loss-of-function approach coupled with gene expression microarray profiling demonstrated that BRD4, KDM3A, and Cohesin are required for the expression of a large portion of ERα target genes [18, 40–42]. GATA3 and FOXA1 have been implied as the pioneer factors for priming the genome-wide distribution of ERα [36, 39].…”

Section: Discussionmentioning

confidence: 99%

Systematic identification of Ctr9 regulome in ERα-positive breast cancer

et al. 2016

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BackgroundWe had previously identified Ctr9, the key scaffold subunit of the human RNA polymerase II (RNAPII) associated factor complex (PAFc), as a key factor regulating a massive ERα target gene expression and ERα-positive breast cancer growth. Furthermore, we have shown that knockdown of Ctr9 reduces ERα protein stability and decreases the occupancy of ERα and RNAPII at a few ERα-target loci. However, it remains to be determined whether Ctr9 controls ERα-target gene expression by regulating the global chromatin occupancy of ERα and RNAPII in the presence of estrogen.ResultsIn this study, we determined the genome-wide ERα and RNAPII occupancy in response to estrogen treatment and/or Ctr9 knockdown by performing chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq). We found that loss of Ctr9 dramatically decreases the global occupancy of ERα and RNAPII, highlighting the significance of Ctr9 in regulating estrogen signaling in ERα-positive breast cancer cells. Combining this resource with previously published genomic data sets, we identified a unique subset of ERα and Ctr9 target genes, and further delineated the independent function of Ctr9 from other subunits in PAFc when regulating transcription.ConclusionsOur data demonstrated that Ctr9, independent of other PAFc subunits, controls ERα-target gene expression by regulating global chromatin occupancies of ERα and RNAPII.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3248-3) contains supplementary material, which is available to authorized users.

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“…Within 30 min of the addition of estrogen, co-regulators such as SRC-1, AIB1, H2A.Z, H2ac, and p300 are rapidly recruited to ERα binding sites to activate the expression of ERα target genes [24,37,38]. Furthermore, ERα can recruit histone demethylase enzymes KDM3A, KDM4B, and KDM6B to ERα targeted chromatin to assert histone modification changes [39–41]. Herein, we demonstrated that a histone methyltranferase, KMT2B, plays a significant role in enhancing the transcriptional activity of ERα through the enrichment of active H3K4 methylation.…”

Section: Discussionmentioning

confidence: 99%

Regulation of IL-20 Expression by Estradiol through KMT2B-Mediated Epigenetic Modification

Su¹,

Lin²,

Tzeng³

et al. 2016

PLoS ONE

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Cytokines are low molecular weight regulatory proteins, or glycoproteins, with both tumor-promoting and inhibitory effects on breast cancer growth. Different cytokines play important roles in breast cancer initiation and progression. Here, we show that of the 39 interleukin (IL) genes, IL-20 is the only gene over-expressed in MCF-7 cells treated with estradiol (E2) and that induction of IL-20 expression by estrogen was epigenetically regulated. Methylation of histone H3K4 in the IL-20 promoter was shown to occur via the specific recruitment of KMT2B by estrogen receptor alpha (ERα), but not by other members of the mixed-lineage leukemia (MLL) family of histone methyltransferases. Depletion of KMT2B, or IL-20, disrupts estrogen signaling, attenuates cell proliferation, reduces colony formation, and results in cell cycle arrest. Furthermore, we demonstrated that KMT2B-mediated epigenetic modification also affected the expression of several ERα target genes. IL-20 and KMT2B expression were also associated with ERα-positive breast cancer tissues. We have revealed an important role for KMT2B in the epigenetic transcriptional regulation of cytokine IL-20, and other ERα-responsive genes, in breast cancer cells. Inhibition of IL-20 and KMT2B may have therapeutic benefits in ERα-positive breast cancer.

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The histone demethylase enzyme KDM3A is a key estrogen receptor regulator in breast cancer

Cited by 89 publications

References 57 publications

Hypoxia-inducible KDM3A addiction in multiple myeloma

Hypoxia-inducible KDM3A addiction in multiple myeloma

Systematic identification of Ctr9 regulome in ERα-positive breast cancer

Regulation of IL-20 Expression by Estradiol through KMT2B-Mediated Epigenetic Modification

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