Abstract 2043: SATB1 (special AT-rich binding protein 1) as a putative therapeutic target in colorectal cancer

Abstract

Abstract The Special AT-rich Binding Protein 1 (SATB1) is a global chromatin organizer that regulates the expression of a large number of genes in direct and indirect manners. By functioning as a “landing platform” for chromatin remodeling enzymes, SATB1 targets chromatin remodeling complexes to DNA at the base of chromatin loops. Thus, SATB1 influences the expression of multiple genes in an epigenetic manner. In several human cancers, SATB1 overexpression has been described and connected to carcinogenesis. Furthermore, the expression of SATB1 correlates with tumor progression and is associated with poor prognosis. Colorectal cancer is one of the most common causes for cancer-related deaths worldwide. Although methods of diagnosis and treatment have improved over the last few decades, the tumor stage at diagnosis is still the most important prognostic marker and the overall survival of patients with advanced colorectal cancer is still poor due to the high risk of metastasis. Therefore, it is critical to determine potential targets for new therapeutic strategies. In this study, we have analyzed the function of SATB1 in primary and in established colorectal cancer cell lines and determined the therapeutic relevance of SATB1-specific gene knockdown approaches by RNA interference (RNAi). In CRC cells, an RNAi-mediated knockdown of the SATB1 was achieved by transient or by stable transfection with specific siRNAs or shRNAs-encoding plasmids, each leading to markedly reduced SATB1 mRNA and protein levels. SATB1 knockdown caused an inhibition of proliferation, a deceleration of cell cycle progression and pro-apoptotic effects. Further analyses revealed effects of SATB1 on multiple signaling pathways influencing e.g. EMT, apoptosis and ErbB receptor expression. The functional relevance of SATB1 (knockdown) was also determined in vivo in an s.c. tumor xenograft model in athymic nude mice, using stable LS174T knockdown cells. Notably, a marked inhibition of tumor growth was observed. Beyond stable established cell lines, studies were extended towards primary colorectal carcinoma cells. Transient siRNA-mediated SATB1 knockdown led to antiproliferative and proapoptotic effects in primary cell lines with different SATB1 expression levels. The therapeutic potential of SATB1 inhibition was further explored in vivo in mice bearing s.c. xenografts. For the induction of therapeutic RNAi in vivo, mice were treated with polymeric nanoparticles containing siRNAs, i.e., polyethylenimine (PEI)/siRNA-complexes. Notably, a marked inhibition of tumor growth was observed in the siRNA treatment group, indicating profound therapeutic effects of SATB1 knockdown in primary colorectal cancer cells. Taken together, these results indicate an important and complex role of SATB1 in the tumorigenesis of colorectal cancer, and establish SATB1 inhibition or siRNA-mediated knockdown as a promising target for pharmacological intervention. Citation Format: Anja Frömberg, Michael Rabe, Michael Linnebacher, Achim M. Aigner. SATB1 (special AT-rich binding protein 1) as a putative therapeutic target in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2043. doi:10.1158/1538-7445.AM2015-2043