Abstract 2042: Cancer-specific transcription factor BORIS has different effects on expression of its target genes via chromatin structure alterations

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL BORIS (Brother of the Regulator of Imprinted Sites), the paralog of insulator CTCF, is male germ line-specific transcription factor. BORIS and CTCF are highly structurally similar and share the same DNA sequence recognition sites. However, unlike widely expressed CTCF, BORIS is repressed in normal tissues and expressed only in testis and in several types of human cancers including head and neck cancers, lung cancers, melanomas and in tumor-derived cell lines. Suprabasin (SBSN) is a protein that is normally expressed only in suprabasal layer of epidermis, and was defined as a potential oncogene in non small cell lung carcinoma. BORIS has been implicated in the activation of cancer-testis antigens (CTA) genes, such as MAGEA1 and NY-ESO-1. Additionally, BORIS is shown to bind hypermethylated DNA sites and alter the DNA methylation state of MAGEA1 promoter. BORIS shows abundant expression in a variety of cancers and its importance in tumorigenesis has been reported. However, there are controversial reports about the role of BORIS on tumorigenesis. Using cell proliferation assays, immunoprecipitation, qPCR, qRT-PCR, QMSP and other techniques we show that SBSN is a newly discovered target of BORIS epigenetic regulation. Induction of low concentrations of BORIS leads to activation of the chromatin around SBSN transcription start site resulting in its 18-35 fold increase in expression in human cancer cell lines, including lung cancer. We have demonstrate that high BORIS concentrations can lead to subsequent repression of SBSN by 2-3 folds via chromatin repression (5-10 fold decrease in presence of active histone modifications, evaluated by ChIP and qPCR) and via DNA hypermethylation (4 folds increase, by QMSP). In a similar manner, overexpression of BORIS leads to eventual repression of other well-known BORIS targets, including NY-ESO-1 and H19. We also show that BORIS induces cell growth at low concentration and inhibits cell growth and colony formation at high concentrations. Our data indicate that BORIS has different effects on target genes depending on its abundance around binding sites. Thus, low BORIS concentration leads to strong target activation and cell proliferation, while higher concentrations leads to repression of the target genes and cell growth inhibition. These data explain the enigmatic controversy of published materials about role of BORIS effect on tumorigenesis. Preliminary data also suggests that there are a group of transcription factors similar to BORIS that can recognize DNA methylation status of the binding sites. Therefore, they might have both stimulating and repressing effects on epigenetic regulation of target genes expression depending on the factor abundance. Molecular analysis of epigenetic mechanisms of action of BORIS and BORIS-like transcription factors might be beneficial for further development of cancer therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2042. doi:10.1158/1538-7445.AM2011-2042