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Abstract
Cellular senescence has been regarded as a mechanism of tumor suppression. Studying the regulation of gene expression at various levels in cell senescence will shed light on cancer therapy. Alternative polyadenylation (APA) regulates gene expression by altering 3′ untranslated regions (3′ UTR) and plays important roles in diverse biological processes. However, whether APA of a specific gene functions in both cancer and senescence remains unclear. Here, we discovered that 3′ UTR of HN1 (or JPT1) showed shortening in cancers and lengthening in senescence, correlated well with its high expression in cancer cells and low expression in senescent cells, respectively. HN1 transcripts with longer 3′ UTR were less stable and produced less protein. Down-regulation of HN1 induced senescence-associated phenotypes in both normal and cancer cells. Patients with higher HN1 expression had lower survival rates in various carcinomas. Interestingly, down-regulating the splicing factor HNRNPA1 induced 3′ UTR lengthening of HN1 and senescence-associated phenotypes, which could be partially reversed by overexpressing HN1. Together, we revealed for the first time that HNRNPA1-mediated APA of HN1 contributed to cancer- and senescence-related phenotypes. Given senescence is a cancer prevention mechanism, our discovery indicates the HNRNPA1-HN1 axis as a potential target for cancer treatment.
Highlights
Alternative polyadenylation (APA) of mRNA is a prevalent post-transcriptional gene regulation mechanism in eukaryotes [1]
By comparing genes preferring shorter 3′ 3′ untranslated region (UTR) in seven cancer types based on RNA-seq (RNA sequencing) datasets from TCGA (The Cancer Genome Atlas) and genes preferring longer 3′ untranslated regions (3′ UTR) in senescent mouse embryonic fibroblasts (MEFs) and rat vascular smooth muscle cells based on polyadenylation sequencing (PA-seq) [16, 17], we screened out 36 genes exhibiting opposite changes in 3′ UTR length between cancer and senescence
By evaluating 3′ UTR length changes with the ΔPDUI (Percentage of Distal polyA site Usage Index) [17], we found Hematopoietic- and neurologic-expressed sequence 1 (HN1) prefered the proximal pA site in six out of seven tested cancers, such as LUSC (Lung squamous cell carcinoma), LUAD (Lung adenocarcinoma), UCEC (Uterine Corpus Endometrial Carcinoma), BLCA (Bladder Urothelial Carcinoma), BRCA (Breast invasive carcinoma), and KIRC (Kidney renal clear cell carcinoma), indicating HN1 underwent a general 3′ UTR shortening in cancer (Figure 1B)
Summary
Alternative polyadenylation (APA) of mRNA is a prevalent post-transcriptional gene regulation mechanism in eukaryotes [1]. SRSF3 (or SRp20), one member of the serine/argininerich (SR) splicing factor family, can regulate the www.aging-us.com alternative pA site recognition of calcitonin coding gene CALCA [7]. HNRNPC, a member of heterogeneous nuclear ribonucleoproteins (HNRNP) family that involved in alternative splicing, has a genome-wide effect on APA regulation of mRNA with poly(U) motifs [8]. Many SR and HNRNP splicing factors are abnormally expressed in a variety of cancer types [9]. Whether they could function in regulating APA and cancer-associated processes remains to be explored
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