Modulation of Oncogenic Transcription and Alternative Splicing by β-Catenin and an RNA Aptamer in Colon Cancer Cells

Abstract

Activated B-catenin regulates the transcription of oncogenic target genes and is critical for tumorigenesis. Because nuclear functions are frequently coupled, we investigated whether it also has a role in alternative splicing of oncogenic genes. We showed that stabilized B-catenin caused alternative splicing of estrogen receptor-B pre-mRNA in colon cancer cells. To establish a direct role of B-catenin in regulated splicing, we selected a high-affinity RNA aptamer that associated with B-catenin in vivo . Nuclear localized aptamer inhibited B-catenin-dependent transcription of cyclin D1 and c-myc in colon cancer cells; thus, cells stably expressing the aptamer exhibited cell cycle arrest and reduced tumor forming potential. Most significantly, the aptamer prevented the alternative splicing induced by stabilized B-catenin. Taken together, our results establish that B-catenin has an important role in both transcription and splicing, and that its action can be modulated by a high-affinity RNA aptamer. The RNA aptamer could be further developed as a specific inhibitor for cancer therapeutics. (Cancer Res 2006; 66(21): 10560-6)

Role of Pinin in neural crest, dorsal dermis, and axial skeleton development and its involvement in the regulation of Tcf/Lef activity in mice

“…Furthermore, ␤-catenin has been recently reported to influence pre-mRNA splicing (Sato et al, 2005;Lee et al, 2006), a process where PNN is also involved (Li et al, 2003;Zimowska et al, 2003). Even though the relevance of these functional commonalities needs further investigation, our in vivo studies may provide a crucial insight into PNN's connection to a signaling pathway, which may govern biological processes in which PNN has been shown to be involved.…”

“…In addition, recent studies suggested that the oncogenic activity of ␤-catenin may include its ability to influence premRNA splicing, thus allowing the production of cancer-associated splicing variants (Sato et al, 2005;Lee et al, 2006;Shitashige et al, 2007).…”

Emerging roles of RNA and RNA-binding protein network in cancer cells

“…In addition, overexpression and unregulated expression of β-catenin regulates RNA alternative splicing and RNA stabilization in colon cancer cells (48)(49)(50). Overexpressed β-catenin upregulates cyclinD1 and c-myc mRNA transcription as transcription factors in cancer cells.…”

FGFR2-related pathogenesis and FGFR2-targeted therapeutics (Review)

“…RNA aptamers are short RNA oligonucleotides forming a stable three-dimensional structure for specific tight binding to target protein (64)(65)(66)(67). RNA aptamers binding to target proteins are selected from combinatorial libraries by using SELEX method.…”