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

Cell Reports (Jul 2022)

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

Journal volume & issue: Vol. 40, no. 4
p. 111066

Abstract

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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.

CP: Cancer

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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