Abstract
The oncogenic properties of heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1) have been reported, although the tumor-promoting mechanism remains unclear. We herein report the mechanism underlying colorectal cancer cell progression mediated by hnRNP H1. The growth of colorectal cancer cells was suppressed by hnRNP H1 downregulation. A terminal deoxynucleotidyl transferase dUTP nick-end labeling assay revealed the anti-apoptotic effect of hnRNP H1 in colorectal cancer cells. An RNA immunoprecipitation assay revealed that hnRNP H1 bound to sphingosine-1-phosphate lyase 1 (SGPL1). Reverse transcription-polymerase chain reaction revealed the high expression of hnRNP H1 mRNA in colorectal cancer cells and Spearman’s rank correlation coefficient showed a strong positive correlation between hnRNP H1 mRNA and SGPL1 mRNA. An siRNA of hnRNP H1 decreased SGPL1 mRNA expression in colorectal cancer cells, but not in non-tumorous cells. These findings suggested that hnRNP H1 increased SGPL1 mRNA expression specifically in cancer cells through direct binding. Targeted knockdown of hnRNP H1 or SGPL1 with siRNAs upregulated p53 phosphorylation and p53-associated molecules, resulting in cell growth inhibition, while hnRNP H1 upregulated the mRNA of SGPL1 and inhibited p53 activation, thereby promoting tumor cell growth. This is a novel mechanism underlying colorectal cancer cell progression mediated by hnRNP H1–SGPL1 mRNA stabilization.
Highlights
Colorectal cancer is one of the most frequent causes of cancer-related death worldwide [1]
We found that Heterogeneous nuclear ribonucleoproteins (hnRNPs) H1 downregulation did not influence the expression of sphingosine-1-phosphate lyase 1 (SGPL1) mRNA in non-tumorous cells, suggesting that hnRNP H1-induced upregulation of SGPL1
Ceramide is considered to be responsible for antiproliferative responses, such as the inhibition of cell growth and induction of apoptosis, while S1P has opposite functions, including the promotion of cancer cell growth and angiogenesis, based on the sphingosine rheostat or ceramide-S1P rheostat theory [8,12,15,16]
Summary
Colorectal cancer is one of the most frequent causes of cancer-related death worldwide [1]. Previous studies have shown that several hnRNPs have oncogenic properties, such as the induction of excess cell growth and exertion of an anti-apoptotic effect [5], but each hnRNP targets different RNAs depending on the cancer type or origin. A study proposed that hnRNP H1 increased the mRNA and protein expression of a-raf, thereby preventing apoptosis [6]. We confirmed the tumor-promoting effect of hnRNP H1 and selected 10,914 mRNAs that bind to hnRNP H1 based on an immunoprecipitation-transcriptome assay in colorectal cancer cells. We found that the p53-related genes cyclin G2 and CDKN1A were dysregulated in SGPL1-downregulated cells, illustrating a novel tumor-promoting mechanism involving hnRNP H1-upregulated SGPL1 mRNA
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