The epigenetic modifier JMJD6 is amplified in mammary tumors and cooperates with c-Myc to enhance cellular transformation, tumor progression, and metastasis

Abstract

BackgroundOncogene overexpression in primary cells often triggers the induction of a cellular safeguard response promoting senescence or apoptosis. Secondary cooperating genetic events are generally required for oncogene-induced tumorigenesis to overcome these biologic obstacles. We employed comparative genomic hybridization for eight genetically engineered mouse models of mammary cancer to identify loci that might harbor genes that enhance oncogene-induced tumorigenesis.ResultsUnlike many other mammary tumor models, the MMTV-Myc tumors displayed few copy number variants except for amplification of distal mouse chromosome 11 in 80 % of the tumors (syntenic to human 17q23-qter often amplified in human breast cancer). Analyses of candidate genes located in this region identified JMJD6 as an epigenetic regulatory gene that cooperates with Myc to enhance tumorigenesis. It suppresses Myc-induced apoptosis under varying stress conditions through inhibition of p19ARF messenger RNA (mRNA) and protein, leading to reduced levels of p53. JMJD6 binds to the p19ARF promoter and exerts its inhibitory function through demethylation of H4R3me2a. JMJD6 overexpression in MMTV-Myc cell lines increases tumor burden, induces EMT, and greatly enhances tumor metastasis. Importantly, we demonstrate that co-expression of high levels of JMJD6 and Myc is associated with poor prognosis for human ER+ breast cancer patients.ConclusionsA novel epigenetic mechanism has been identified for how JMJD6 cooperates with Myc during oncogenic transformation. Combined high expression of Myc and JMJD6 confers a more aggressive phenotype in mouse and human tumors. Given the pleiotropic pro-tumorigenic activities of JMJD6, it may be useful as a prognostic factor and a therapeutic target for Myc-driven mammary tumorigenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0205-6) contains supplementary material, which is available to authorized users.

JMJD6 Licenses ERα-Dependent Enhancer and Coding Gene Activation by Modulating the Recruitment of the CARM1/MED12 Co-activator Complex

“…Indeed, JMJD6 has been found to be highly expressed in clinical ERα-positive breast tumor samples (Aprelikova et al, 2016, Lee et al, 2012, Poulard et al, 2015). JMJD6 has been shown to possess, at least two types of enzymatic activities, demethylation (Liu et al, 2013, Chang et al, 2007) and hydroxylation (Webby et al, 2009), which are important for its function in gene transcription and splicing.…”

“…Besides its function in transcriptional control, we and others have shown that JMJD6 also interacts with multiple splicing factors, and is involved in gene splicing control (Heim et al, 2014, Webby et al, Liu et al, 2013, Rahman et al, 2011, Yi et al, 2017). JMJD6 has been implicated in a multitude of biological processes, including embryonic development (Bose et al, 2004, Li et al, 2003, Kunisaki et al, 2004), cell cycle control (Wang et al, 2014a), cellular proliferation and motility (Lee et al, 2012, Chen et al, 2014), adipocyte differentiation (Hu et al, 2015) and development of various types of cancers, such as breast (Poulard et al, 2015, Lee et al, 2012, Aprelikova et al, 2016), lung (Zhang et al, 2013) and colon cancer (Wang et al, 2014a). …”

The role of epigenetic changes in preeclampsia

“…JMJD6 could demethylate the histone arginine marks . Moreover, studies showed that the JMJD6 demethylase enzyme dimethylated histone 3 at arginine 2 (H3R2me2s), and histone 4 at arginine 3 (H3R2me2s) . JMJD6 expression significantly increased in PE .…”

Jumonji domain‐containing protein 6 protein and its role in cancer

“…Furthermore, p19ARF binds with Myc and prevents Myc‐mediated tumorigenesis in a p53‐independent manner . JMJD6 cooperates with Myc to enhance tumorigenesis through suppressing Myc‐induced apoptosis . JMJD6 binds to the p19ARF promoter and demethylates Arg3 of histone H4, thereby repressing p19ARF and reducing p53 levels.…”

“…12 In both ER+ and ER− breast cancer patients, elevated expression of JMJD6 is positively associated with histological grade, age, lymph node metastasis, tumour size and advanced tumour node metastasis (TNM). 12,62 Unfavourable survival was observed in high JMJD6 expressers with ER+ breast cancer. 10,62 However, in ER− breast cancer patients, several studies have reported that there is no significant correlation between JMJD6 level and survival, probably due to the high level of JMJD6 expression in ER− breast cancer.…”