Abstract
IntroductionBreast cancer is a worldwide health problem and the leading cause of cancer death among females. We previously identified Jumonji domain containing 2A (JMJD2A) as a critical mediator of breast cancer proliferation, migration and invasion. We now report that JMJD2A could promote breast cancer progression through transcriptional repression of the tumor suppressor aplasia Ras homolog member I (ARHI).MethodsImmunohistochemistry was performed to examine protein expressions in 155 cases of breast cancer and 30 non-neoplastic tissues. Spearman correlation analysis was used to analyze the correlation between JMJD2A expression and clinical parameters as well as several tumor regulators in 155 cases of breast cancer. Gene and protein expressions were monitored by quantitative polymerase chain reaction (qPCR) and Western blot. Results from knockdown of JMJD2A, overexpression of JMJD2A, Co-immunoprecipitation (Co-IP) assay, dual luciferase reporter gene assay and chromatin immunoprecipitation (ChIP) elucidated molecular mechanisms of JMJD2A action in breast cancer progression. Furthermore, the effects of ARHI overexpression on JMJD2A-mediated tumor progression were investigated in vitro and in vivo. For in vitro experiments, cell proliferation, wound-healing, migration and invasion were monitored by cell counting, scratch and Boyden Chamber assays. For in vivo experiments, control cells and cells stably expressing JMJD2A alone or together with ARHI were inoculated into mammary fat pads of mice. Tumor volume, tumor weight and metastatic nodules were measured by caliper, electronic balance and nodule counting, respectively.ResultsJMJD2A was highly expressed in human breast cancers and positively correlated with tumor progression. Knockdown of JMJD2A increased ARHI expression whereas overexpression of JMJD2A decreased ARHI expression at both protein and mRNA levels. Furthermore, E2Fs and histone deacetylases were involved in the transcriptional repression of ARHI expression by JMJD2A. And the aggressive behavior of JMJD2A in breast cancers could be reversed by re-expression of ARHI in vitro and in vivo.ConclusionWe demonstrated a cancer-promoting effect of JMJD2A and defined a novel molecular pathway contributing to JMJD2A-mediated breast cancer progression.
Highlights
Breast cancer is a worldwide health problem and the leading cause of cancer death among females
Expression of Jumoji domain containing 2A (JMJD2A) is positively correlated with progression of breast cancer and negatively with tumor suppressor Aplasia Ras homolog member I (ARHI) To determine whether the expression level of JMJD2A was associated with progression of breast cancer, we initially examined JMJD2A expression in four breast cancer cell lines, including two weakly metastatic cell lines (MCF-7 and T47D) and two highly metastatic cell lines (MDA-MB-231 and SUM1315)
Our results showed that Estrogen receptor alpha (ERα) and progesterone receptor (PR) were stained mainly in the nuclei and Human epidermal growth factor receptor-2 (HER2) was localized in the cell membrane, whereas ARHI was mainly in the cell membrane and partially in the cytoplasm (Figure 3B and D)
Summary
Breast cancer is a worldwide health problem and the leading cause of cancer death among females. We report that JMJD2A could promote breast cancer progression through transcriptional repression of the tumor suppressor aplasia Ras homolog member I (ARHI). Demethylation of different lysine residues may result in activated or repressed transcription. Due to its activity to demethylate diand tri-methylation on a variety of histone lysine residues, such as H3K9 and H3K36 [11], H3K4 and H4K20 [12,13], JMJD2A can modify chromatin structure and function as a transcriptional repressor or activator. Recent evidence shows that JMJD2A positively regulates the expression of ADAM12, CXCL5 and JAG1 genes through histone H3K9me demethylation [15]. JMJD2A is reported to be a novel N-CoR interacting protein, leading to transcriptional repression of downstream genes like ASCL2 [16]
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