Abstract
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 language | English (US) |
---|---|
Article number | 111066 |
Journal | Cell Reports |
Volume | 40 |
Issue number | 4 |
DOIs | |
State | Published - Jul 26 2022 |
Keywords
- 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)