Research Paper Volume 11, Issue 13 pp 4407—4437

HNRNPA1-mediated 3′ UTR length changes of HN1 contributes to cancer- and senescence-associated phenotypes

Qi Jia 1, , Hongbo Nie 2, , Peng Yu 1, , Baiyun Xie 1, , Chenji Wang 3, , Fu Yang 4, , Gang Wei 1, , Ting Ni 1, ,

  • 1 State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai 200438, P.R. China
  • 2 Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, P.R. China
  • 3 State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200438, P.R. China
  • 4 Department of Medical Genetics, Second Military Medical University, Shanghai 200433, P.R. China

received: March 9, 2018 ; accepted: June 24, 2019 ; published: June 30, 2019 ;

https://doi.org/10.18632/aging.102060
How to Cite

Copyright: Jia et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.

Abbreviations

HN1: Hematopoietic- and neurologic-expressed sequence 1; HNRNPA1: Heterogeneous Nuclear Ribonucleoprotein A1; 3′ UTR: 3′ untranslated region; RBP: RNA binding protein; miRNA: MicroRNA; lncRNA: long noncoding RNA; rRNA: ribosomal RNA; RNA-seq: RNA sequencing; PA-seq: polyadenylation sequencing; DaPars: Dynamic analyses of Alternative PolyAdenylation from RNA-Seq; 3′ READS: 3′ region extraction and deep sequencing; TCGA: The Cancer Genome Atlas; LIHC: Liver Hepatocellular Carcinoma; LUSC: Lung squamous cell carcinoma; LUAD: Lung adenocarcinoma; UCEC: Uterine Corpus Endometrial Carcinoma; BLCA: Bladder Urothelial Carcinoma; BRCA: Breast invasive carcinoma; KIRC: Kidney renal clear cell carcinoma; KIRP: Kidney renal papillary cell carcinoma; ACC: Adrenocortical carcinoma; HNSC: Head and Neck squamous cell carcinoma; PAAD: Pancreatic adenocarcinoma; SKCM: Skin Cutaneous Melanoma; PDUI: Percentage of Distal polyA site Usage Index; 3′ RACE: 3′ rapid amplification of cDNA ends; qRT-PCR: Quantitative reverse transcription polymerase reaction; APA: Alternative polyadenylation; AS: Alternative splicing; CCK-8: Cell counting kit-8; EdU: 5-Ethynyl-20- deoxyuridine; RIP: RNA immunoprecipitation; SA-β-Gal: senescence-associated beta-galactosidase; ROS: reactive oxygen species; KD: knock down; IgG: immunoglobulin G; HUVEC: Human umbilical vein endothelial cells; MEF: Mouse Embryonic Fibroblast; rVSMC: rat vascular smooth muscle cells; HFF: human foreskin fibroblasts; ALS: amyotrophic lateral sclerosis.