The histone arginine demethylase JMJD6 is over-expressed in brain metastatic breast cancer.

Control of gene expression includes regulation by trans-acting transcription factors and cis-acting epigenetic regulation by chemical modification of histones and the DNA (1, 2). Brain metastases are a clinical problem in patients with breast cancer (3-5). We mined published microarray data (6, 7) to discover genes associated with brain metastasis in patients with brain metastatic breast cancer. We found that the gene encoding the histone arginine demethylase JMJD6 was among the genes most differentially expressed in the brain metastases of patients with brain metastatic breast cancer. JMJD6 may be of relevance to the biology underlying metastasis to the brain, and it may be of relevance as a potential therapeutic target in patients with intractable disease.

Nuclear hnRNPA2B1 initiates and amplifies the innate immune response to DNA viruses

DNA viruses typically eject genomic DNA into the nuclei of host cells after entry. It is unclear, however, how nuclear pathogen–derived DNA triggers innate immune responses. We report that heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) recognizes pathogenic DNA and amplifies interferon-α/β (IFN-α/β) production. Upon DNA virus infection, nuclear-localized hnRNPA2B1 senses viral DNA, homodimerizes, and is then demethylated at arginine-226 by the arginine demethylase JMJD6. This results in hnRNPA2B1 translocation to the cytoplasm where it activates the TANK-binding kinase 1–interferon regulatory factor 3 (TBK1–IRF3) pathway, leading to IFN-α/β production. Additionally, hnRNPA2B1 facilitates N6-methyladenosine (m6A) modification and nucleocytoplasmic trafficking of CGAS, IFI16, and STING messenger RNAs. This, in turn, amplifies the activation of cytoplasmic TBK1–IRF3 mediated by these factors. Thus, hnRNPA2B1 plays important roles in initiating IFN-α/β production and enhancing stimulator of interferon genes (STING)–dependent cytoplasmic antiviral signaling.

JMJD6 induces HOTAIR, an oncogenic lincRNA, by physically interacting with its proximal promoter

Using microarray analysis, we found that HOX transcript antisense intergenic RNA (HOTAIR) is up-regulated by Jumonji domain containing-6 (JMJD6), a bifunctional lysyl hydroxylase and arginine demethylase. In breast cancer, both JMJD6 and HOTAIR RNAs increase tumor growth and associate with poor prognosis but no molecular relationship between them is known. We show that overexpression of JMJD6 increased HOTAIR expression and JMJD6 siRNAs suppressed it in ER+ MCF-7, triple negative MDA-MB-231 and non-breast cancer HEK 293 cells. Therefore, JMJD6 regulates HOTAIR independent of ER status. Using various deletion constructs spanning (−1874 to +50) of the HOTAIR promoter, we identified pHP216 (−216 to +50 bp) as the smallest construct that retained maximal JMJD6 responsiveness. In ChIP assays, JMJD6 bound this region suggesting that JMJD6 may be directly recruited to the HOTAIR promoter. Mutant JMJD6H187A that is devoid of enzymatic activity could bind this site but failed to induce transcription. ChIP and electromobility shift assays identified a JMJD6 interaction region from (−123 to −103 bp) within the HOTAIR promoter. In tumor samples but not normal breast tissue, the expression of JMJD6 linearly correlated with HOTAIR suggesting that JMJD6-mediated up-regulation may occur specifically in tumors. Further, concurrent high expression of both genes correlated with poor survival when individual expression of either gene showed no significant association in TCGA datasets. We propose that high JMJD6 expression may achieve higher levels of HOTAIR in breast tumors. Further, since high levels of HOTAIR promote metastasis and death, blocking JMJD6 may be useful in preventing such events.