Genome‐wide investigation of intragenic DNA methylation identifies ZMIZ1 gene as a prognostic marker in glioblastoma and multiple cancer types

Abstract

DNA methylation has long been recognized as a tumor‐promoting factor when aberrantly regulated in the promoter region of genes. However, the effect of intragenic DNA methylation remains poorly understood on the clinical aspects of cancer. Here, we first evaluated the significance of intragenic DNA methylation for survival outcomes of cancer patients in a genome‐wide manner. Glioblastoma patients with hypermethylated intragenic regions exhibited better survival than hypomethylated patients. Enrichment analyses of intragenic DNA methylation profiles with epigenetic signatures prioritized the intragenic DNA methylation of ZMIZ1 as a possible glioblastoma prognostic marker that is independent of MGMT methylation in IDH1 wild‐type patients. This intragenic region harbored molecular signatures of alternative transcription across many cell types. Furthermore, we found that the intragenic region of ZMIZ1 can serve as a molecular marker in multiple cancers including astrocytomas, bladder cancer and renal cell carcinoma according to DNA methylation status. Finally, in vitro and in vivo experiments uncovered the role of ZMIZ1 as a driver of tumor cell migration. Altogether, our results identify ZMIZ1 as a prognostic marker in cancer and highlight the clinical significance of intragenic methylation in cancer.

Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression

“…The possible redundancy of ZMIZ oncoproteins in the keratinocyte transformation program, by mutual exclusivity of trunk insertions within cuSCC genomes, strongly suggests that the ZMIZ1 ΔN185 and ZMIZ2 ΔN184 oncoproteins may have common neomorphic properties that contribute to the hallmarks of skin cancer. The work of Rogers et al (Rogers et al, 2013), and more recently Mathios et al (Mathios et al, 2019), on the dynamic regulation of ZMIZ1 expression in human cancer, together with our finding that ZMIZ1 and ZMIZ2 are mutated with at least on non-silent alteration in at least one third of published human cuSCC genomes (Pickering et al, 2014;South et al, 2014) and, suggest that this gene may be an important initiating trunk mutation in human keratinocyte initiation and cuSCC progression. Transcriptome analysis on SB-driven cuSCCs with high read depth insertions in Zmiz1 or Zmiz2 to detected SB transposon fusions to both drivers.…”

JKAMP inhibits the osteogenic capacity of adipose-derived stem cells in diabetic osteoporosis by modulating the Wnt signaling pathway through intragenic DNA methylation

“…DNA methylation of CGI near these putative promoters also silences these genes [32]. Mathios et al found that intragenic DNA methylation of glioblastoma may also be a regulatory mechanism of ZMIZ1 gene transcription [56]. Interestingly, in our study, we found that the promoter of JKAMP showed no obvious difference in the DNA methylation degree between CON-ASCs and DOP-ASCs.…”

JKAMP Inhibits the Osteogenic Capacity of Adipose-derived Stem Cells in Diabetic Osteoporosis by Modulating the Wnt Signaling Pathway Through Intragenic DNA Methylation

“…DNA methylation of CGI near these putative promoters also silences these genes [31]. Mathios et al found that intragenic DNA methylation of glioblastoma may also be a regulatory mechanism of ZMIZ1 gene transcription [54]. Interestingly, in our study, we found that the promoter of JKAMP showed no obvious difference in the DNA methylation degree between CON-ASCs and DOP-ASCs.…”