Abstract 698: The loss of SATB2 promotes ulcerative colitis-related colon cancer progression through altered localized inflammatory response

Abstract

Abstract SATB2 is a member of a family of special AT-rich binding proteins and a novel transcription factor that orchestrates gene expression in a tissue-specific manner by regulating higher-order chromatin structure. Here, we assess the precise functional role of SATB2 in the development and progression of colorectal cancer, initiating from the proinflammatory phenotype. Differential expression of SATB2 was observed in colorectal cancer, with loss of expression occurring sequentially along the adenoma-carcinoma sequence, with the early preneoplastic tissue demonstrating highest SATB2 levels, which diminishes within adenomas followed by complete loss of SATB2 expression in metastatic disease. Functionally, we demonstrate that siRNA-mediated knockdown of SATB2 in SW480 cells was associated with the acquisition of an aggressive phenotype. Consistent with these findings, loss of SATB2 protein and mRNA expression was determined as an independent predictor of poor prognosis in 3 independent CRC cohorts (n=776). Furthermore, gene set enrichment analysis in two of these independent colorectal cancer cohorts revealed that loss of SATB2 mRNA expression was associated with a TH2 cytokine response and checkpoint genes like CTLA4 and PD1 and modulation of SATB2 expression in CRC cell lines led to altered expression of proinflammatory cytokines. Within this context, following classification of the patient samples within these cohorts into the recently published consensus molecular subtypes (CMS) revealed that SATB2 levels were significantly lower in the CMS1 subtype that effectively represents the immune subtype of colorectal cancer. In addition, tissue microarray (TMA) analysis of a sigmoidal colorectal cancer TMA representing 350 colorectal cancer patients demonstrated that lower SATB2 levels with poor outcome and inversely correlated with CD68+ infiltrates. Intriguingly, SATB2 expression was associated with chromosomal stability as knockdown of SATB2 resulted in an increase of anaphase bridging, which was independent of telomere length and directly related to the spindle assembly complex. Given the relationship between SATB2, chromosomal instability and local inflammatory response, SATB2 protein expression was assessed in a large cohort of patients with ulcerative colitis (UC), some of whom developed UC-related carcinoma. SATB2 protein expression decreased across the disease spectrum from normal to UC to dysplasia to carcinoma, suggesting that SATB2 expression can be used to monitor UC patients at risk of developing CRC. The findings from this study for the first time demonstrate the role of SATB2 as potential master immune-regulator in colon cancer and its pivotal role in regulating key inflammatory factors facilitating the progression of colorectal cancer initiating from a proinflammatory phenotype. Citation Format: Sudipto Das, Kirsha Naicker, Rut Klinger, Yue Fan, Girish Mallya, Fredrick Ponten, Karin Jirström, Jacintha O'Sullivan, William M. Gallagher, Donal J. Brenan, Darran P. O'Connor. The loss of SATB2 promotes ulcerative colitis-related colon cancer progression through altered localized inflammatory response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 698.