Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival

Fan, Lingling; Peng, Guihong; Sahgal, Natasha; Fazli, Ladan; Gleave, Martin; Zhang, Yuji; Hussain, Arif; Qi, Jianfei

doi:10.1038/onc.2015.309

Cited by 94 publications

(108 citation statements)

References 47 publications

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“…Overall 37.0% of the AR ChIP-Seq peaks with altered H3K9me1/2 signal were suppressed upon knockdown of KDM3A , while the remaining fraction was not affected. The genome-wide ChIP-Seq analysis is consistent with the biochemical data, demonstrating that KDM3A in effect recruited AR to target genes [3, 18]. KDM3A ChIP-Seq and H3K9me1/2-KDM ChIP-Seq in combination with matched knockdown of KDM3A produced an epigenetic network that overlaid with the AR ChIP-Seq data (Figure 4H–4J).…”

Section: Resultssupporting

confidence: 76%

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The histone demethylaseKDM3Aregulates the transcriptional program of the androgen receptor in prostate cancer cells

et al. 2017

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The lysine demethylase 3A (KDM3A, JMJD1A or JHDM2A) controls transcriptional networks in a variety of biological processes such as spermatogenesis, metabolism, stem cell activity, and tumor progression. We matched transcriptomic and ChIP-Seq profiles to decipher a genome-wide regulatory network of epigenetic control by KDM3A in prostate cancer cells. ChIP-Seq experiments monitoring histone 3 lysine 9 (H3K9) methylation marks show global histone demethylation effects of KDM3A. Combined assessment of histone demethylation events and gene expression changes presented major transcriptional activation suggesting that distinct oncogenic regulators may synergize with the epigenetic patterns by KDM3A. Pathway enrichment analysis of cells with KDM3A knockdown prioritized androgen signaling indicating that KDM3A plays a key role in regulating androgen receptor activity. Matched ChIP-Seq and knockdown experiments of KDM3A in combination with ChIP-Seq of the androgen receptor resulted in a gain of H3K9 methylation marks around androgen receptor binding sites of selected transcriptional targets in androgen signaling including positive regulation of KRT19, NKX3-1, KLK3, NDRG1, MAF, CREB3L4, MYC, INPP4B, PTK2B, MAPK1, MAP2K1, IGF1, E2F1, HSP90AA1, HIF1A, and ACSL3. The cancer systems biology analysis of KDM3A-dependent genes identifies an epigenetic and transcriptional network in androgen response, hypoxia, glycolysis, and lipid metabolism. Genome-wide ChIP-Seq data highlights specific gene targets and the ability of epigenetic master regulators to control oncogenic pathways and cancer progression.

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Section: Resultssupporting

confidence: 76%

“…Knockdown of KDM3A had little effect on the protein level of AR [3, 18]. We examined the alteration of AR binding by ChIP-Seq with an AR antibody following KDM3A knockdown and quantified the overlap of AR ChIP-Seq events with KDM3A binding and changes in epigenetic H3K9me1/2 marks (Figure 4A–4D).…”

Section: Resultsmentioning

confidence: 99%

The histone demethylaseKDM3Aregulates the transcriptional program of the androgen receptor in prostate cancer cells

et al. 2017

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“…In addition, mutation or upregulation of c‐Myc affects tumorigenesis (Hu, Banerjee, & Goss DJ, ). For example, c‐Myc overexpression is associated with various human cancers, including breast cancer (Ren et al, ), NSCLC (Rapp et al, ), and prostate cancer (Fan et al, ).…”

Section: Introductionmentioning

confidence: 99%

Deubiquitinating enzyme USP22 positively regulates c‐Myc stability and tumorigenic activity in mammalian and breast cancer cells

Kim

Hong

Park

et al. 2017

Journal Cellular Physiology

115

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The proto-oncogene c-Myc has a pivotal function in growth control, differentiation, and apoptosis and is frequently affected in human cancer, including breast cancer. Ubiquitin-specific protease 22 (USP22), a member of the USP family of deubiquitinating enzymes (DUBs), mediates deubiquitination of target proteins, including histone H2B and H2A, telomeric repeat binding factor 1, and cyclin B1. USP22 is also a component of the mammalian SAGA transcriptional co-activating complex. In this study, we explored the functional role of USP22 in modulating c-Myc stability and its physiological relevance in breast cancer progression. We found that USP22 promotes deubiquitination of c-Myc in several breast cancer cell lines, resulting in increased levels of c-Myc. Consistent with this, USP22 knockdown reduces c-Myc levels. Furthermore, overexpression of USP22 stimulates breast cancer cell growth and colony formation, and increases c-Myc tumorigenic activity. In conclusion, the present study reveals that USP22 in breast cancer cell lines increases c-Myc stability through c-Myc deubiquitination, which is closely correlated with breast cancer progression.

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“…CTCF was previously shown to be associated with AR binding (45), but this interaction was contingent upon loss of FOXA1 and subsequent expansion of AR cistrome; thus, the present data bring forth new understanding of CTCF-AR interplay. Additionally, the c-myc motif was exclusively enriched in early G1; this motif was shown to be enriched in AR binding in clinical CRPC samples (46) and is known to be important for PCa survival, up-regulated in PCa, and associated with aggressive disease (47–50). As AR and c-myc are also known to regulate similar metabolic pathways (51), and have been seen to co-regulate target genes (52), the phase specific enrichment provides the context to determine how these two major transcriptional effectors of cancer progression act in concert to promote disease progression.…”

Section: Discussionmentioning

confidence: 99%

Cell cycle-coupled expansion of AR activity promotes cancer progression

et al. 2016

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The androgen receptor (AR) is required for prostate cancer (PCa) survival and progression, and ablation of AR activity is the first line of therapeutic intervention for disseminated disease. While initially effective, recurrent tumors ultimately arise for which there is no durable cure. Despite the dependence of PCa on AR activity throughout the course of disease, delineation of the AR-dependent transcriptional network that governs disease progression remains elusive, and the function of AR in mitotically active cells is not well understood. Analyzing AR activity as a function of cell cycle revealed an unexpected and highly expanded repertoire of AR-regulated gene networks in actively cycling cells. New AR functions segregated into two major clusters: those that are specific to cycling cells and retained throughout the mitotic cell cycle (“Cell Cycle Common”), versus those that were specifically enriched in a subset of cell cycle phases (“Phase Restricted”). Further analyses identified previously unrecognized AR functions in major pathways associated with clinical PCa progression. Illustrating the impact of these unmasked AR-driven pathways, dihydroceramide-desaturase 1 (DEGS1) was identified as an AR regulated gene in mitotically active cells that promoted pro-metastatic phenotypes, and in advanced PCa proved to be highly associated with development of metastases, recurrence after therapeutic intervention, and reduced overall survival. Taken together, these findings delineate AR function in mitotically active tumor cells, thus providing critical insight into the molecular basis by which AR promotes development of lethal PCa and nominate new avenues for therapeutic intervention.

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Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival

Cited by 94 publications

References 47 publications

The histone demethylaseKDM3Aregulates the transcriptional program of the androgen receptor in prostate cancer cells

The histone demethylaseKDM3Aregulates the transcriptional program of the androgen receptor in prostate cancer cells

Deubiquitinating enzyme USP22 positively regulates c‐Myc stability and tumorigenic activity in mammalian and breast cancer cells

Cell cycle-coupled expansion of AR activity promotes cancer progression

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