The epigenetic factor BORIS (CTCFL) controls the androgen receptor regulatory network in ovarian cancer

Abstract

The identification of prognostic biomarkers is a priority for patients suffering from high-grade serous ovarian cancer (SOC), which accounts for >70% of ovarian cancer (OC) deaths. Meanwhile, borderline ovarian cancer (BOC) is a low malignancy tumor and usually patients undergo surgery with low probabilities of recurrence. However, SOC remains the most lethal neoplasm due to the lack of biomarkers for early diagnosis and prognosis. In this regard, BORIS ( CTCFL ), a CTCF paralog, is a promising cancer biomarker that is overexpressed and controls transcription in several cancer types, mainly in OC. Studies suggest that BORIS has an important function in OC by altering gene expression, but the effect and extent to which BORIS influences transcription in OC from a genome-wide perspective is unclear. Here, we sought to identify BORIS target genes in an OC cell line (OVCAR3) with potential biomarker use in OC tumor samples. To achieve this, we performed in vitro knockout and knockdown experiments of BORIS in OVCAR3 cell line followed by expression microarrays and bioinformatics network enrichment analysis to identify relevant BORIS target genes. In addition, ex vivo expression data analysis of 373 ovarian cancer patients were evaluated to identify the expression patterns of BORIS target genes. In vitro, we uncovered 130 differentially expressed genes and obtained the BORIS-associated regulatory network, in which the androgen receptor (AR) acts as a major transcription factor. Also, FN1 , FAM129A , and CD97 genes, which are related to chemoresistance and metastases in OC, were identified. In SOC patients, we observed that malignancy is associated with high levels of BORIS expression while BOC patients show lower levels. Our study suggests that BORIS acts as a main regulator, and has the potential to be used as a prognostic biomarker and to yield novel drug targets among the genes BORIS controls in SOC patients.

GATA4 regulates epithelial morphogenesis in the developing mouse stomach to promote establishment of a glandular columnar epithelium

“…PKNOX1, which preferentially binds to promoter sequences, represses adipogenic differentiation and is implicated in negative regulation of the GLUT4 gene (Longobardi et al 2014;Maroni et al 2017;Ciccarelli et al 2016). BORIS negatively regulates an androgen receptor regulatory network in ovarian cancer (Salgado-Albarrán et al 2019). Finally, PIT-1 functions with nuclear receptor co-repressor N-CoR to repress gene expression (Scully et al 2000;Sporici et al 2005).…”

“…although not yet definitively linked with GATA4, have transcriptional activities aligning with the GATA4 neighborhoods in which they were identified, i.e., positive regulators in activated genes or negative regulators in repressed genes (Rhie et al 2018;Ni et al 2020;Jheon et al 2001;Kasaai et al 2013;Watson, Tekki-Kessaris, and Boulter 2000;Longobardi et al 2014;Maroni et al 2017;Ciccarelli et al 2016;Salgado-Albarrán et al 2019;Scully et al 2000;Sporici et al 2005).…”

Construction and validation of a robust epigenetic gene-set based signature in ovarian cancer

“…The readers are in charge of recognizing the speci c modi cations and the erasers play the of wiping out these chemical modi cations. A great deal of epigenetic alterations mediated by speci c epigenetic factors have been proved as prognostic biomarker in OC [14][15][16][17][18]. However, no previous studies analyzed these epigenetic factors comprehensively to assess the prognostic value of the entire gene set of epigenetic factors.…”

Defining the relative and combined contribution of CTCF and CTCFL to genomic regulation

“…It is also aberrantly activated in cancers of several lineages including lung [13–15], breast [16, 17], uterine [18], esophageal [19], hepatocellular [20], ovarian [21–24], prostate [25], urogenital [26] and neuroblastoma [27]. CTCFL has been shown to promote neoplastic transformations by its interference in cellular processes including invasion and apoptosis, cell proliferation and immortalization [21, 22, 27–29]. Furthermore, CTCFL was identified as one of the most promising cancer testis antigens by the NCI [30] and it is known to be important in activating the expression of numerous other cancer testis antigens.…”