XPO7 is a tumor suppressor regulating p21CIP1-dependent senescence.

Andrew J Innes,Andrew J Innes,Joaquim Pombo,Bin Sun,Bin Sun,Ramón García-Escudero,Ramón García-Escudero,Ramón García-Escudero,Sharon Brookes,Jean-Baptiste Vannier,Jean-Baptiste Vannier,Joaquim Pombo,Gopuraja Dharmalingam,Johannes Zuber,Sharon Brookes,Rosa María Porreca,Domhnall Mchugh,Gopuraja Dharmalingam,Verena Wagner,Verena Wagner,Jesús Gil,Jesús Gil,Domhnall Mchugh,Rosa María Porreca,Santiago Vernia

doi:10.1101/gad.343269.120

Abstract

Senescence is a key barrier to neoplastic transformation. To identify senescence regulators relevant to cancer, we screened a genome-wide shRNA library. Here, we describe exportin 7 (XPO7) as a novel regulator of senescence and validate its function in telomere-induced, replicative, and oncogene-induced senescence (OIS). XPO7 is a bidirectional transporter that regulates the nuclear-cytoplasmic shuttling of a broad range of substrates. Depletion of XPO7 results in reduced levels of TCF3 and an impaired induction of the cyclin-dependent kinase inhibitor p21CIP1 during OIS. Deletion of XPO7 correlates with poorer overall survival in several cancer types. Moreover, depletion of XPO7 alleviated OIS and increased tumor formation in a mouse model of liver cancer. Our results suggest that XPO7 is a novel tumor suppressor that regulates p21CIP1 expression to control senescence and tumorigenesis.

Highlights

Senescence is a stress response that limits the replication of old, damaged, or preneoplastic cells
Replicative senescence of primary human fibroblasts is a stochastic process in part triggered by telomere attrition (Harley et al 1990)
Expression of TRF2ΔBΔM resulted in increased DNA damage (Supplemental Fig. S1a) that accumulates at telomeres (Fig. 1D)

Summary

Introduction

Senescence is a stress response that limits the replication of old, damaged, or preneoplastic cells. P16INK4a, another CDKI is up-regulated during senescence and, together with p21CIP1, contributes to arrest of senescent cells. The activation of the p53/p21CIP1 and p16INK4a/Rb tumor suppressor pathways underlies the implementation of the senescence growth arrest. Components of these pathways are among the most frequently altered genes in cancer, underlining the functional relationship between senescence and cancer. OIS occurs in premalignant lesions and limits tumorigenesis by arresting preneoplastic cells (Collado et al 2005) and activating SASP-dependent. We have screened for shRNAs blunting senescence induction To this end, we have taken advantage of a dominant negative mutant of the shelterin component TRF2 to cause telomere dysfunction and trigger senescence (Jacobs and de Lange 2004).

Methods

Results

Conclusion