Suppression of p16 alleviates the senescence-associated secretory phenotype

Aging (Albany NY). 2021 Feb 6;13(3):3290-3312. doi: 10.18632/aging.202640. Epub 2021 Feb 6.

Abstract

Oncogene-induced senescence (OIS) is characterized by increased expression of the cell cycle inhibitor p16, leading to a hallmark cell cycle arrest. Suppression of p16 in this context drives proliferation, senescence bypass, and contributes to tumorigenesis. OIS cells are also characterized by the expression and secretion of a widely variable group of factors collectively termed the senescence-associated secretory phenotype (SASP). The SASP can be both beneficial and detrimental and affects the microenvironment in a highly context-dependent manner. The relationship between p16 suppression and the SASP remains unclear. Here, we show that knockdown of p16 decreases expression of the SASP factors and pro-inflammatory cytokines IL6 and CXCL8 in multiple models, including OIS and DNA damage-induced senescence. Notably, this is uncoupled from the senescence-associated cell cycle arrest. Moreover, low p16 expression in both cancer cell lines and patient samples correspond to decreased SASP gene expression, suggesting this is a universal effect of loss of p16 expression. Together, our data suggest that p16 regulates SASP gene expression, which has implications for understanding how p16 modulates both the senescent and tumor microenvironment.

Keywords: LMNB1; inflammation; interleukin-6; interleukin-8; melanoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Checkpoints / genetics
  • Cell Line, Tumor
  • Cellular Senescence / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16* / genetics
  • Cyclin-Dependent Kinase Inhibitor p16* / metabolism
  • Gene Knockdown Techniques
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism
  • Lamin Type B / metabolism

Substances

  • CDKN2A protein, human
  • CXCL8 protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • IL6 protein, human
  • Interleukin-6
  • Interleukin-8
  • Lamin Type B
  • lamin B1