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

7 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

Biochemistry, Genetics and Molecular Biology(all)

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

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.",

keywords = "BMP2, BMP9, CP: Cancer, SMAD, SOX2, TGF-β, anchorage independence, anoikis, metastasis, ovarian cancer, pigenetic",

author = "Zainab Shonibare and Mehri Monavarian and Kathleen O'Connell and Diego Altomare and Abigail Shelton and Shubham Mehta and Renata Jaskula-Sztul and Rebecca Phaeton and Starr, {Mark D.} and Regina Whitaker and Andrew Berchuck and Nixon, {Andrew B.} and Arend, {Rebecca C.} and Lee, {Nam Y.} and Miller, {C. Ryan} and Nadine Hempel and Karthikeyan Mythreye",

note = "Funding Information: We thank Pratik Patel and Drs. A. Varadaraj, L. Vaughn, M. Gatza, E. Listik, S. Murphy, Z. Huang, S. Pradhan, and S. Varambally for discussions, technical assistance, and gifts of cell lines and EZH2 inhibitor. Graphical abstract was made with Biorender.com . Imaging was supported by the UAB HRIF . Funding provided by NIH R01CA230628 to K.M. and N.H., and Ovarian Cancer Research Alliance{\textquoteright}s Liz Tilberisgrant to K.M. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

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doi = "10.1016/j.celrep.2022.111066",

language = "English (US)",

volume = "40",

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T1 - Reciprocal SOX2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer

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

N1 - Funding Information: We thank Pratik Patel and Drs. A. Varadaraj, L. Vaughn, M. Gatza, E. Listik, S. Murphy, Z. Huang, S. Pradhan, and S. Varambally for discussions, technical assistance, and gifts of cell lines and EZH2 inhibitor. Graphical abstract was made with Biorender.com . Imaging was supported by the UAB HRIF . Funding provided by NIH R01CA230628 to K.M. and N.H., and Ovarian Cancer Research Alliance’s Liz Tilberisgrant to K.M. Publisher Copyright: © 2022 The Authors

PY - 2022/7/26

Y1 - 2022/7/26

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.

KW - BMP2

KW - BMP9

KW - CP: Cancer

KW - SMAD

KW - SOX2

KW - TGF-β

KW - anchorage independence

KW - anoikis

KW - metastasis

KW - ovarian cancer

KW - pigenetic

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DO - 10.1016/j.celrep.2022.111066

M3 - Article

C2 - 35905726

AN - SCOPUS:85135213169

SN - 2211-1247

VL - 40

JO - Cell Reports

JF - Cell Reports

IS - 4

M1 - 111066

ER -

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

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