c-Myb and C/EBPβ regulate OPN and other senescenceassociated secretory phenotype factors

Kevin C. Flanagan, Elise Alspach, Ermira Pazolli, Shankar Parajuli, Qihao Ren, Laura L. Arthur, Roberto Tapia, Sheila A. Stewart

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Tumorigenesis results from the convergence of cell autonomous mutations and corresponding stromal changes that promote tumor cell growth. Senescent cells, which secrete a plethora of pro-tumorigenic factors termed the senescence-associated secretory phenotype (SASP), play an important role in tumor formation. Investigation into SASP regulation revealed that many but not all SASP factors are subject to NF-kB and p38MAPK regulation. However, many pro-tumorigenic SASP factors, including osteopontin (OPN), are not responsive to these canonical pathways leaving the regulation of these factors an open question. We report that the transcription factor c-Myb regulates OPN, IL-6, and IL-8 in addition to 57 other SASP factors. The regulation of OPN is direct as c-Myb binds to the OPN promoter in response to senescence. Further, OPN is also regulated by the known SASP regulator C/EBPβ. In response to senescence, the full-length activating C/EBPβ isoform LAP2 increases binding to the OPN, IL-6, and IL-8 promoters. The importance of both c-Myb and C/ EBPβ is underscored by our finding that the depletion of either factor reduces the ability of senescent fibroblasts to promote the growth of preneoplastic epithelial cells.

Original languageEnglish
Pages (from-to)21-36
Number of pages16
JournalOncotarget
Volume9
Issue number1
DOIs
StatePublished - Jan 1 2018

Keywords

  • C-Myb
  • C/EBPβ
  • Osteopontin
  • SASP
  • Senescence

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    Flanagan, K. C., Alspach, E., Pazolli, E., Parajuli, S., Ren, Q., Arthur, L. L., Tapia, R., & Stewart, S. A. (2018). c-Myb and C/EBPβ regulate OPN and other senescenceassociated secretory phenotype factors. Oncotarget, 9(1), 21-36. https://doi.org/10.18632/oncotarget.22940