XPO7 is a tumor suppressor regulating p21CIP1-dependent senescence

Genes Dev. 2021 Mar 1;35(5-6):379-391. doi: 10.1101/gad.343269.120. Epub 2021 Feb 18.

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.

Keywords: TCF3; XPO7; functional screen; p21CIP1; senescence; tumor suppressor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Line, Tumor
  • Cellular Senescence / genetics*
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Female
  • Gene Expression Regulation, Developmental / genetics
  • Gene Knockdown Techniques
  • Humans
  • Karyopherins / genetics*
  • Karyopherins / metabolism*
  • Mice
  • Neoplasms / physiopathology
  • Telomeric Repeat Binding Protein 2 / genetics
  • ran GTP-Binding Protein / genetics*
  • ran GTP-Binding Protein / metabolism*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Cyclin-Dependent Kinase Inhibitor p21
  • Karyopherins
  • TCF3 protein, human
  • Telomeric Repeat Binding Protein 2
  • XPO7 protein, human
  • ran GTP-Binding Protein