Abstract
The RNA binding protein CELF1 (also known as CUGBP1) is emerging as a critical regulator of cancer cell proliferation and apoptosis. Here, to provide a global prospective of CELF1 regulation of oral squamous cell carcinoma, we performed RNA-sequencing in oral cancer cells and CELF1 overexpression analysis in non-malignant human oral keratinocytes. Our approaches identified 1283 mRNAs differentially regulated as a function of CELF1 expression and more importantly CELF1 promoted alternative splicing of several target pre-mRNAs, which are known to be involved in various cancer biological processes. Overexpression of CELF1 in non-malignant human oral keratinocytes protected cells against oxidative damage and altered gene expression patterns. Finally, we provide evidence that reduction of CELF1 protein using a xenograft tumorigenesis mouse model decreased tumor growth. Altogether, these data provided a comprehensive view of the CELF1 mRNA regulatory network in oral cancer and suggests that CELF1 and/or its target mRNAs are viable candidates for therapeutic intervention.
Highlights
The human genome consist of approximately 424 predicted RNA binding proteins (RBPs), and only a few have been extensively characterized for their role in cancer [1]
In this study, utilizing generation sequencing in CELF1 depleted oral cancer cells, we identified mRNA targets that were both directly and indirectly controlled by CELF1
We demonstrated that in oral cancer cells CELF1 controls the expression of 1283 mRNAs that were enriched in biological terms associated with cell proliferation and apoptosis, which was not surprising
Summary
The human genome consist of approximately 424 predicted RNA binding proteins (RBPs), and only a few have been extensively characterized for their role in cancer [1]. RBPs are critical regulators of co- and post- transcriptional gene expression and are capable of associating with both messenger RNAs and non-coding RNAs [2]. RBPs associate with their mRNA targets by binding to specific sequence motifs and/or recognizing distinct RNA secondary structures [3]. The RNA-binding activity and the expression level of RBPs can be rapidly modulated in response to external stimuli, via post-translational modifications [6]. The RBP HuR is implicated in tumorigenesis and tumor cell survival [7, 8]. Altered expression of RBPs are noted in oral squamous cell carcinoma (OSCC) [8, 12, 13], raising the possibility that disruption of post-transcriptional regulation may contribute to oral cancer tumorigenesis
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