Artikel
SATB1 as a putative therapeutic target in colorectal cancer
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Veröffentlicht: | 25. September 2014 |
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Gliederung
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Aim: Colorectal cancer is one of the most common causes for cancer-related deaths worldwide. Therefore, it is critical to determine potential targets for new therapeutic strategies.
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.
The aim of this study was to analyzed the function of SATB1 in primary and in established colorectal cancer cell lines.
Method: We determined the therapeutic relevance of SATB1-specific gene knockdown approaches by RNA interference (RNAi). In LS174T cells and primary HROC24 cells, RNAi-mediated knockdown of SATB1 was achieved by transient or stable transfection with specific siRNAs or shRNA-encoding plasmids, which led to markedly reduced SATB1 mRNA and protein levels.
Results: SATB1 knockdown caused inhibition of proliferation, deceleration of cell cycle and pro-apoptotic effects in a gene-dose dependent manner. Further analyses regarding the underlying cellular mechanisms revealed effects of SATB1 on multiple signaling pathways influencing e.g. EMT, apoptosis and ErbB receptor expression. The in vivo relevance of SATB1 was demonstrated in an s.c. tumor xenograft model in athymic nude mice, using LS174T cells with stable SATB1 knockdown.
The therapeutic potential of SATB1 inhibition was further explored in vivo in mice bearing s.c. xenografts from primary HROC24 cells. 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.
Conclusion: Taken together, these results indicate an important and complex role of SATB1 in the tumorigenesis of colorectal cancer, and establish SATB1 inhibition or knockdown as a promising target for pharmacological intervention.
References
- 1.
- Frömberg A, Rabe M, Aigner A. Multiple effects of the Special AT-rich Binding Protein 1 (SATB1) in colon carcinoma. Int J Cancer. 2014.