Mdig promotes oncogenic gene expression through antagonizing repressive histone methylation markers

Abstract

The mineral dust-induced gene (mdig) is overexpressed in a number of human cancers, suggesting critical roles of this gene played on the pathogenesis of cancers. Unlike several other JmjC-domain containing proteins that exhibit histone demethylase activity, it remains enigmatic whether mdig is involved in the demethylation processes of the histone proteins.Methods: To provide direct evidence suggesting contribution of mdig to the demethylation of histone proteins, we recently examined the histone methylation profiles in human bronchial epithelial cells as well as two cancer cell lines with mdig knockout through CRISPR-Cas9 gene editing.Results: Global histone methylation analysis revealed a pronounced increase of the repressive histone trimethylation in three different cell types with mdig depletion, including trimethylation of lysines 9 and 27 on histone H3 (H3K9me3, H3K27me3) and trimethylation of lysine 20 of histone H4 (H4K20me3). Importantly, data from both ChIP-seq and RNA-seq suggested that genetic disruption of mdig enriches repressive histone trimethylation and inhibits expression of target genes in the oncogenic pathways of cell growth, stemness of the cells, tissue fibrosis, and cell motility.Conclusion: Taken together, our study provides the first insight into the molecular effects of mdig as an antagonist for repressive histone methylation markers and suggests that targeting mdig may represent a new area to explore in cancer therapy.

Targeted inhibition of KDM6 histone demethylases eradicates tumor-initiating cells via enhancer reprogramming in colorectal cancer

“…Methylation at different histone residue sites gives distinct impact on transcriptional activity and high-order chromatin structure. Proper control of H3K27me3 level and its distribution pattern across different genomic features are essential for embryonic development and maintenance of physiological homeostasis, which frequently goes awry during tumorigenesis 12 , 37 , 38 . Therefore, the feasibility of targeting molecules keeping the balance of H3K27me3 for cancer therapeutics has been under evaluation for a long time, such as EZH2 inhibitors 14 , 39 .…”

Genome-wide scan for selection signatures reveals novel insights into the adaptive capacity in local North African cattle

“…Similarly, the most relevant selection signal in the AFT/North AFT comparison (BTA06 at position: 46,780,000-50,050,000 bp) harboured one protein coding gene (PCDH7) which coincides with a known CNV ( Supplementary Table S4), one 5S ribosomal RNA (5S rRNA) and three non-coding RNA genes: SNORA70, Y_RNA and U6 (Table 1). PCDH7 is one of the key genes involved in oncogenesis and/or differentiation of the cancer stem cells through a change in its histone methylation status 49 . Likewise, 5S rRNA genes are highly methylated in Arabidopsis thaliana and their expression is under epigenetic control 50,51 .…”

Loss of SUV420H2 promotes EGFR inhibitor resistance in NSCLC through upregulation of MET via LINC01510

“…Apart from SUV39H1/2, it is also possible that other upstream regulators of SUV420H2 such as HP1 may have an unidentified role in mediating resistance to drugs, such as EGFRi (Bosch-Presegué et al, 2017;Hahn et al, 2013). Indeed, the first identified demethylase for H4K20me3, mineral dust-induced gene (Mdig) was determined to be overexpressed in breast and lung cancer cells antagonizing the effects of the H4K20me3 modification which led to induction of oncogenes (Zhang et al, 2020). Analogous to Mdig overexpression in cancer cells, leading to reduction of H4K20me3, we found that loss of SUV420H2 also leads to depletion of H4K20me3 mark that in turn enhances oncogenes such as LINC01510 and MET.…”