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
Affiliations
Zainab Shonibare
Department of Pathology, O’Neal Comprehensive Cancer Center, University of Alabama School of Medicine, Birmingham, AL, USA; Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA
Mehri Monavarian
Department of Pathology, O’Neal Comprehensive Cancer Center, University of Alabama School of Medicine, Birmingham, AL, USA
Kathleen O’Connell
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA
Diego Altomare
Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA
Abigail Shelton
Department of Pathology, O’Neal Comprehensive Cancer Center, Comprehensive Neuroscience Center, University of Alabama School of Medicine, Birmingham, AL, USA
Shubham Mehta
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA
Renata Jaskula-Sztul
Department of Surgery, University of Alabama School of Medicine, Birmingham, AL, USA
Rebecca Phaeton
Department of Obstetrics and Gynecology, and Microbiology and Immunology, College of Medicine, Pennsylvania State University, Hershey, PA, USA
Mark D. Starr
Department of Medicine and Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
Regina Whitaker
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA
Andrew Berchuck
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA
Andrew B. Nixon
Department of Medicine and Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
Rebecca C. Arend
Department of Gynecology Oncology, University of Alabama School of Medicine, Birmingham, AL, USA
Nam Y. Lee
Department of Chemistry and Biochemistry, Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA
C. Ryan Miller
Department of Pathology, O’Neal Comprehensive Cancer Center, Comprehensive Neuroscience Center, University of Alabama School of Medicine, Birmingham, AL, USA
Nadine Hempel
Department of Pharmacology, and Obstetrics and Gynecology, College of Medicine, Pennsylvania State University, Hershey, PA, USA; Department of Medicine, Division of Hematology Oncology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA; Corresponding author
Karthikeyan Mythreye
Department of Pathology, O’Neal Comprehensive Cancer Center, University of Alabama School of Medicine, Birmingham, AL, USA; Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA; Corresponding author
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.
