Reciprocal SOX2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer

Zainab Shonibare, Mehri Monavarian, Kathleen O'Connell, Diego Altomare, Abigail Shelton, Shubham Mehta, Renata Jaskula-Sztul, Rebecca Phaeton, Mark D. Starr, Regina Whitaker, Andrew Berchuck, Andrew B. Nixon, Rebecca C. Arend, Nam Y. Lee, C. Ryan Miller, Nadine Hempel, Karthikeyan Mythreye

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Growth factors in tumor environments are regulators of cell survival and metastasis. Here, we reveal the dichotomy between TGF-β superfamily growth factors BMP and TGF-β/activin and their downstream SMAD effectors. Gene expression profiling uncovers SOX2 as a key contextual signaling node regulated in an opposing manner by BMP2, -4, and -9 and TGF-β and activin A to impact anchorage-independent cell survival. We find that SOX2 is repressed by BMPs, leading to a reduction in intraperitoneal tumor burden and improved survival of tumor-bearing mice. Repression of SOX2 is driven by SMAD1-dependent histone H3K27me3 recruitment and DNA methylation at SOX2’s promoter. Conversely, TGF-β, which is elevated in patient ascites, and activin A can promote SOX2 expression and anchorage-independent survival by SMAD3-dependent histone H3K4me3 recruitment. Our findings identify SOX2 as a contextual and contrastingly regulated node downstream of TGF-β members controlling anchorage-independent survival and metastasis in ovarian cancers.

Original languageEnglish (US)
Article number111066
JournalCell Reports
Issue number4
StatePublished - Jul 26 2022


  • BMP2
  • BMP9
  • CP: Cancer
  • SMAD
  • SOX2
  • TGF-β
  • anchorage independence
  • anoikis
  • metastasis
  • ovarian cancer
  • pigenetic

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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