Reciprocal SOX2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer
2022
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
Summary: 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.
Show more [+] Less [-]Bibliographic information
This bibliographic record has been provided by Directory of Open Access Journals