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bioRxiv · 10.1101/2022.01.11.475900

Reciprocal epigenetic Sox2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer

SHONIBARE, Z.·Monavarian, M.·O'Connell, K.·Altomare, D.·Shelton, A. K.·Mehta, S.·Jaskula-Sztul, R.·Phaeton, R.·Starr, M. D.·Whitaker, R.·Berchuck, A.·Nixon, A.·Arend, R. C.·Lee, N. Y.·Miller, C. R.·Hempel, N.·Mythreye, K.
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Abstract

Growth factors in the tumor environment are key regulators of cell survival and metastasis. Here we reveal, dichotomy between TGF-{beta} superfamily growth factors BMP and TGF-{beta}/activin, and their downstream SMAD effectors. Gene expression profiling uncovered Sox2 as a key signaling node regulated in an opposing manner by anoikis-promoting BMP2, 4 and 9, and anoikis-suppressing TGF-{beta} and activin A. We find that Sox2 repression by BMPs robustly inhibits intraperitoneal tumor burden and increases survival in multiple ovarian cancer models. Repression of Sox2 is driven by SMAD1 dependent histone H3K27me3 recruitment and DNA methylation at SOX2s promoter. Conversely, TGF-{beta} and activin A promote Sox2 expression, and anoikis resistance by SMAD3 mediated histone H3K4me3 recruitment. We find that balancing Sox2 levels is critical for anoikis, as transcriptomics reveals regulation of key cell death pathways. Moreover, BMP-driven SMAD1 signaling can override TGF-{beta} and activins effect on Sox2, which has clinical significance due to the high levels of TGF-{beta} we find in ovarian cancer patients. Together, our findings identify Sox2 as a contextual and contrastingly regulated key node, downstream of TGF-{beta} superfamily members controlling anoikis and metastasis in ovarian cancers. HighlightsO_LISox2 is a key node for anoikis resistance in cancer C_LIO_LISox2 is differentially regulated by TGF-{beta}/activin and BMPs in broad cancers C_LIO_LIBMP9 is a robust metastasis suppressor by lowering Sox2 C_LIO_LISox2 regulation is contextual, epigenetic and at the transcriptional level C_LI

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SHONIBARE, Z., Monavarian, M., O'Connell, K., Altomare, D., Shelton, A. K., Mehta, S., Jaskula-Sztul, R., Phaeton, R., Starr, M. D., Whitaker, R., Berchuck, A., Nixon, A., Arend, R. C., Lee, N. Y., Miller, C. R., Hempel, N., Mythreye, K.. 2022-01-12. Reciprocal epigenetic Sox2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer. https://doi.org/10.1101/2022.01.11.475900

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