Reciprocal SOX2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer
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 r...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-07-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124722008646 |
| _version_ | 1818163364705075200 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Zainab Shonibare |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T16:48:23Z |
| format | Article |
| id | doaj.art-20e1a0843b1f45028091a733956f68ac |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T16:48:23Z |
| publishDate | 2022-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-20e1a0843b1f45028091a733956f68ac2022-12-22T00:58:10ZengElsevierCell Reports2211-12472022-07-01404111066Reciprocal SOX2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancerZainab Shonibare0Mehri Monavarian1Kathleen O’Connell2Diego Altomare3Abigail Shelton4Shubham Mehta5Renata Jaskula-Sztul6Rebecca Phaeton7Mark D. Starr8Regina Whitaker9Andrew Berchuck10Andrew B. Nixon11Rebecca C. Arend12Nam Y. Lee13C. Ryan Miller14Nadine Hempel15Karthikeyan Mythreye16Department 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, USADepartment of Pathology, O’Neal Comprehensive Cancer Center, University of Alabama School of Medicine, Birmingham, AL, USADepartment of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USADepartment of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USADepartment of Pathology, O’Neal Comprehensive Cancer Center, Comprehensive Neuroscience Center, University of Alabama School of Medicine, Birmingham, AL, USADepartment of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USADepartment of Surgery, University of Alabama School of Medicine, Birmingham, AL, USADepartment of Obstetrics and Gynecology, and Microbiology and Immunology, College of Medicine, Pennsylvania State University, Hershey, PA, USADepartment of Medicine and Duke Cancer Institute, Duke University Medical Center, Durham, NC, USADepartment of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USADepartment of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USADepartment of Medicine and Duke Cancer Institute, Duke University Medical Center, Durham, NC, USADepartment of Gynecology Oncology, University of Alabama School of Medicine, Birmingham, AL, USADepartment of Chemistry and Biochemistry, Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USADepartment of Pathology, O’Neal Comprehensive Cancer Center, Comprehensive Neuroscience Center, University of Alabama School of Medicine, Birmingham, AL, USADepartment 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 authorDepartment 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124722008646CP: Cancer |
| spellingShingle | 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 Reciprocal SOX2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer Cell Reports CP: Cancer |
| title | Reciprocal SOX2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer |
| title_full | Reciprocal SOX2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer |
| title_fullStr | Reciprocal SOX2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer |
| title_full_unstemmed | Reciprocal SOX2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer |
| title_short | Reciprocal SOX2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer |
| title_sort | reciprocal sox2 regulation by smad1 smad3 is critical for anoikis resistance and metastasis in cancer |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124722008646 |
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