BORIS Expression in Ovarian Cancer Precursor Cells Alters the CTCF Cistrome and Enhances Invasiveness through GALNT14

Abstract

High-grade serous carcinoma (HGSC) is the most aggressive and predominant form of epithelial ovarian cancer and the leading cause of gynecologic cancer-related death. We have previously shown that CTCFL (also known as BORIS, Brother of the Regulator of Imprinted Sites) is expressed in most ovarian cancers, and is associated with global and promoter-specific DNA hypomethylation, advanced tumor stage, and poor prognosis. To explore its role in HGSC, we expressed BORIS in human fallopian tube secretory epithelial cells (FTSEC), the presumptive cells of origin for HGSC. BORISexpressing cells exhibited increased motility and invasion, and BORIS expression was associated with alterations in several cancer-associated gene expression networks, including fatty acid metabolism, TNF signaling, cell migration, and ECMreceptor interactions. Importantly, GALNT14, a glycosyltransferase gene implicated in cancer cell migration and invasion, was highly induced by BORIS, and GALNT14 knockdown significantly abrogated BORIS-induced cell motility and invasion. In addition, in silico analyses provided evidence for BORIS and GALNT14 coexpression in several cancers. Finally, ChIP-seq demonstrated that expression of BORIS was associated with de novo and enhanced binding of CTCF at hundreds of loci, many of which correlated with activation of transcription at target genes, including GALNT14. Taken together, our data indicate that BORIS may promote cell motility and invasion in HGSC via upregulation of GALNT14, and suggests BORIS as a potential therapeutic target in this malignancy.Implications: These studies provide evidence that aberrant expression of BORIS may play a role in the progression to HGSC by enhancing the migratory and invasive properties of FTSEC.

The Role of the Meiotic Component in Reproduction of B-RAF-Mutated Melanoma: A Review and “Brainstorming” Session

“…Notably, emerging evidence has shown that BORIS functions as an epigenetic modifier in modulating the whole genome gene expression [113][114][115], including expression of other CT genes [116,117]. BORIS was also found to be expressed in embryonal carcinoma, ovarian cancer [118] as well as cancer stem cell (CSC)-enriched populations isolated from epithelial cancer cells [119,120]. The mRNA isoforms of BORIS genes are expressed in normal ovary and in the altered pattern, in epithelial ovarian cancer [121].…”

Global DNA Hypomethylation in Epithelial Ovarian Cancer: Passive Demethylation and Association with Genomic Instability

“…Supporting this idea, DNA hypomethylation and genomic alterations are associated in human cancer [23][24][25][26][27][28]. Second, aberrant gene expression, including oncogene activation, RE expression, or CG antigen gene activation may promote oncogenic phenotypes and/or disease progression [2,[29][30][31][32]. Third, GDHO and the associated hypomethylated block formation may promote gene expression variability and provide a selective growth advantage to the effected cancer cells [33].In addition to identifying the genomic targets and biological consequences of GDHO, it is important to also understand its origin.…”

GALNT14: An Emerging Marker Capable of Predicting Therapeutic Outcomes in Multiple Cancers

“…Both miR-125a mimics and GALNT14 siRNA suppressed the activity of matrix metalloproteinase (MMP)-2 and MMP-9, further inhibiting extracellular matrix degradation. A recent study showed that aberrant expression of BORIS (Brother of the Regulator of Imprinted Sites) altered cell migration and invasion via upregulation of GALNT14, suggesting that BORIS is a potential therapeutic target in ovarian high-grade serous carcinoma [43].…”