Abstract
The SR protein splicing factor SRSF1 is a potent proto-oncogene that is frequently upregulated in cancer. Here, we show that SRSF1 is a direct target of the transcription factor oncoprotein MYC. These two oncogenes are significantly coexpressed in lung carcinomas, and MYC knockdown downregulates SRSF1 expression in lung-cancer cell lines. MYC directly activates transcription of SRSF1 through two noncanonical E-boxes in its promoter. The resulting increase in SRSF1 protein is sufficient to modulate alternative splicing of a subset of transcripts. In particular, MYC induction leads to SRSF1-mediated alternative splicing of the signaling kinase MKNK2 and the transcription factor TEAD1. SRSF1 knockdown reduces MYC's oncogenic activity, decreasing proliferation and anchorage-independent growth. These results suggest a mechanism for SRSF1 upregulation in tumors with elevated MYC and identify SRSF1 as a critical MYC target that contributes to its oncogenic potential by enabling MYC to regulate the expression of specific protein isoforms through alternative splicing.
Highlights
The SR protein splicing factor SRSF1 is a potent proto-oncogene that is frequently upregulated in cancer
Among eight other known or putative MYCregulated splicing factors we analysed (David et al, 2010; Li et al, 2003; Rauch et al, 2011; Zeller et al, 2003) only hnRNPH1 and PTBP1 expression correlated significantly with MYC expression in these lung-tumor samples (Table S1). We extended this analysis to a panel of normal and tumor-derived lung cell lines, and found a significant correlation at the protein level between MYC and SRSF1 (Figure 1B), with most cancer cell lines overexpressing both proteins, relative to IMR90 primary lung fibroblasts
MYC expression did not correlate in these cells with that of other SR proteins, such as SRSF9 (Figure 1B) and SRSF6. siRNA-mediated knockdown of MYC in two of these cell lines, the large cell lung cancer cell line NCI.H460 and the bronchoalveolar adenocarcinoma cell line NCI.H1666, resulted in significant decreases in SRSF1 expression, both at the transcript and protein level, indicating that SRSF1 expression is under MYC control (Figure 1C,D)
Summary
The SR protein splicing factor SRSF1 is a potent proto-oncogene that is frequently upregulated in cancer. We extended this analysis to a panel of normal and tumor-derived lung cell lines, and found a significant correlation at the protein level between MYC and SRSF1 (Figure 1B), with most cancer cell lines overexpressing both proteins, relative to IMR90 primary lung fibroblasts.
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