HnRNP A1 antagonizes cellular senescence and senescence-associated secretory phenotype via regulation of SIRT1 mRNA stability.

Hui Wang,Ganye Zhao,Limin Han,Jun Chen,Chenzhong Xu,Tanjun Tong,Zhaomeng Sun,Guodong Li,Hong Shen,Pengfeng Wang,Yuanyuan Su

doi:10.1111/acel.12511

Abstract

SummarySenescent cells display a senescence‐associated secretory phenotype (SASP) which contributes to tumor suppression, aging, and cancer. However, the underlying mechanisms for SASP regulation are not fully elucidated. SIRT1, a nicotinamide adenosine dinucleotide‐dependent deacetylase, plays multiple roles in metabolism, inflammatory response, and longevity, etc. However, its posttranscriptional regulation and its roles in cellular senescence and SASP regulation are still elusive. Here, we identify the RNA‐binding protein hnRNP A1 as a posttranscriptional regulator of SIRT1, as well as cell senescence and SASP regulator. hnRNP A1 directly interacts with the 3′ untranslated region of SIRT1 mRNA, promotes its stability, and increases SIRT1 expression. hnRNP A1 delays replicative cellular senescence and prevents from Ras OIS via upregulation of SIRT1 expression to deacetylate NF‐κB, thus blunting its transcriptional activity and subsequent IL‐6/IL‐8 induction. hnRNP A1 overexpression promotes cell transformation and tumorigenesis in a SIRT1‐dependent manner. Together, our findings unveil a novel posttranscriptional regulation of SIRT1 by hnRNP A1 and uncover a critical role of hnRNP A1‐SIRT1–NF‐κB pathway in regulating cellular senescence and SASP expression.

Highlights

Cellular senescence, including oncogene-induced cellular senescence (OIS), is a stable cell cycle arrest which limits the proliferation of damaged cells and acts as a natural barrier against tumor development in vivo (Collado & Serrano, 2010)
We further demonstrate that hnRNP A1 can suppress cellular senescence and senescence-associated secretory phenotype (SASP) induction, which depends on SIRT1-mediated deacetylation of NF-jB
Mass spectrometry analysis indicated that hnRNP A1, a RNAbinding protein, was in the presence of the SIRT1 mRNA interactome (Fig. 1A)

Summary

Introduction

Cellular senescence, including oncogene-induced cellular senescence (OIS), is a stable cell cycle arrest which limits the proliferation of damaged cells and acts as a natural barrier against tumor development in vivo (Collado & Serrano, 2010). Many SASP factors including key components IL-6 and IL-8 are mainly regulated at transcriptional level by transcription factor NF-jB (Acosta et al, 2008; Kuilman et al, 2008). Despite various signaling pathways participate in regulating SASP production by altering NF-jB pathway components phosphorylation status and activities (Wang et al, 2014; Kang et al, 2015), little is known about whether NF-jB itself and its activity are subjected to other posttranslational modifications and regulations during senescence. Whether the acetylation status of NF-jB is altered during senescence, whether NF-jB acetylation has effect on the SASP expression, and how NF-jB acetylation is regulated during senescence remain largely unknown

Results

Discussion

Conclusion