CBX7 binds the E-box to inhibit TWIST-1 function and inhibit tumorigenicity and metastatic potential

Abstract

Deaths from ovarian cancer usually occur when patients succumb to overwhelmingly numerous and widespread micrometastasis. Whereas epithelial–mesenchymal transition is required for epithelial ovarian cancer cells to acquire metastatic potential, the cellular phenotype at secondary sites and the mechanisms required for the establishment of metastatic tumors are not fully determined. Using in vitro and in vivo models we show that secondary epithelial ovarian cancer cells (sEOC) do not fully reacquire the molecular signature of the primary epithelial ovarian cancer cells from which they are derived. Despite displaying an epithelial morphology, sEOC maintains a high expression of the mesenchymal effector, TWIST-1. TWIST-1 is however transcriptionally nonfunctional in these cells as it is precluded from binding its E-box by the PcG protein, CBX7. Deletion of CBX7 in sEOC was sufficient to reactivate TWIST-1-induced transcription, prompt mesenchymal transformation, and enhanced tumorigenicity in vivo. This regulation allows secondary tumors to achieve an epithelial morphology while conferring the advantage of prompt reversal to a mesenchymal phenotype upon perturbation of CBX7. We also describe a subclassification of ovarian tumors based on CBX7 and TWIST-1 expression, which predicts clinical outcomes and patient prognosis.

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Fig. 1: Derivation of secondary epithelial ovarian cancer cells (sEOC) in vivo and in vitro.
Fig. 2: sEOC is molecularly distinct from the primary epithelial ovarian cancer cells.
Fig. 3: TWIST-1 is inactive in the sEOC.
Fig. 4: Loss of CBX7 in sEOC is sufficient to promote a mesenchymal phenotype and induce TWIST-1 target genes.
Fig. 5: CBX7 binds to mir-199A promoter region at or near the TWIST-1 binding site.
Fig. 6: Loss of CBX7 leads to enhanced metastatic potential and enhanced TWIST-1 activity in vivo.
Fig. 7: Loss of TWIST-1 leads to decreased metastatic potential.
Fig. 8: CBX7 is positive predictor of survival in TWIST-1pos patients.

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Acknowledgements

This study is supported in part by grants from NIH NCI R01CA199004 (GM), The National Natural Science Foundation of China No. 81572900 (GY), The National Key R&D Program of China, Stem Cell and Translation Research No. 2016YFA0102000 (GY), and Hunan Provincial Natural Science Foundation of China No. 2018JJ3820 (JL).

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JL: performance of experiments, data collection, data analysis, writing of paper; AA: design of experiment, development of experimental model systems, data analysis and interpretation, writing and editing paper; SN, RT, CR, MP, YL, QX, SZ, YG: performance of experiments, data collection, data analysis; GM and GY: conception, design of experiment, development of experimental model systems, data analysis and interpretation, writing and editing paper.

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Correspondence to Gil Mor or Gang Yin.

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Li, J., Alvero, A.B., Nuti, S. et al. CBX7 binds the E-box to inhibit TWIST-1 function and inhibit tumorigenicity and metastatic potential. Oncogene 39, 3965–3979 (2020). https://doi.org/10.1038/s41388-020-1269-5

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