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

doi:10.1016/j.celrep.2022.111066

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

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

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	https://doi.org/10.1016/j.celrep.2022.111066
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

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2022.111066

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Shonibare, Z., Monavarian, M., O'Connell, K., Altomare, D., Shelton, A., Mehta, S., Jaskula-Sztul, R., Phaeton, R., Starr, M. D., Whitaker, R., Berchuck, A., Nixon, A. B., Arend, R. C., Lee, N. Y., Miller, C. R., Hempel, N., & Mythreye, K. (2022). Reciprocal SOX2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer. Cell Reports, 40(4), Article 111066. https://doi.org/10.1016/j.celrep.2022.111066

Shonibare, Z, Monavarian, M, O'Connell, K, Altomare, D, Shelton, A, Mehta, S, Jaskula-Sztul, R, Phaeton, R, Starr, MD, Whitaker, R, Berchuck, A, Nixon, AB, Arend, RC, Lee, NY, Miller, CR, Hempel, N & Mythreye, K 2022, 'Reciprocal SOX2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer', Cell Reports, vol. 40, no. 4, 111066. https://doi.org/10.1016/j.celrep.2022.111066

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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{\textquoteright}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.",

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AU - Shonibare, Zainab

AU - Monavarian, Mehri

AU - O'Connell, Kathleen

AU - Altomare, Diego

AU - Shelton, Abigail

AU - Mehta, Shubham

AU - Jaskula-Sztul, Renata

AU - Phaeton, Rebecca

AU - Starr, Mark D.

AU - Whitaker, Regina

AU - Berchuck, Andrew

AU - Nixon, Andrew B.

AU - Arend, Rebecca C.

AU - Lee, Nam Y.

AU - Miller, C. Ryan

AU - Hempel, Nadine

AU - Mythreye, Karthikeyan

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N2 - 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.

AB - 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.

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KW - pigenetic

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Reciprocal SOX2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer

Abstract

Keywords

ASJC Scopus subject areas

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