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The Epigenetic Regulatory Protein CBX2 Promotes mTORC1 Signalling and Inhibits DREAM Complex Activity to Drive Breast Cancer Cell Growth

Bilton, Lucie J.; Warren, Chloe; Humphries, Rebecca M.; Kalsi, Shannon; Waters, Ella; Francis, Thomas; Dobrowinski, Wojtek; Beltran-Alvarez, Pedro; Wade, Mark A.

Authors

Lucie J. Bilton

Chloe Warren

Rebecca M. Humphries

Shannon Kalsi

Ella Waters

Thomas Francis

Wojtek Dobrowinski



Abstract

Chromobox 2 (CBX2) is a chromatin-binding component of polycomb repressive complex 1, which causes gene silencing. CBX2 expression is elevated in triple-negative breast cancer (TNBC), for which there are few therapeutic options. Here, we aimed to investigate the functional role of CBX2 in TNBC. CBX2 knockdown in TNBC models reduced cell numbers, which was rescued by ectopic expression of wild-type CBX2 but not a chromatin binding-deficient mutant. Blocking CBX2 chromatin interactions using the inhibitor SW2_152F also reduced cell growth, suggesting CBX2 chromatin binding is crucial for TNBC progression. RNA sequencing and gene set enrichment analysis of CBX2-depleted cells identified downregulation of oncogenic signalling pathways, including mTORC1 and E2F signalling. Subsequent analysis identified that CBX2 represses the expression of mTORC1 inhibitors and the tumour suppressor RBL2. RBL2 repression, in turn, inhibits DREAM complex activity. The DREAM complex inhibits E2F signalling, causing cell senescence; therefore, inhibition of the DREAM complex via CBX2 may be a key oncogenic driver. We observed similar effects in oestrogen receptor-positive breast cancer, and analysis of patient datasets suggested CBX2 inhibits RBL2 activity in other cancer types. Therapeutic inhibition of CBX2 could therefore repress mTORC1 activation and promote DREAM complex-mediated senescence in TNBC and could have similar effects in other cancer types.

Citation

Bilton, L. J., Warren, C., Humphries, R. M., Kalsi, S., Waters, E., Francis, T., …Wade, M. A. (2022). The Epigenetic Regulatory Protein CBX2 Promotes mTORC1 Signalling and Inhibits DREAM Complex Activity to Drive Breast Cancer Cell Growth. Cancers, 14(14), Article 3491. https://doi.org/10.3390/cancers14143491

Journal Article Type Article
Acceptance Date Jul 15, 2022
Online Publication Date Jul 18, 2022
Publication Date Jul 2, 2022
Deposit Date Sep 21, 2022
Publicly Available Date Oct 27, 2022
Journal Cancers
Electronic ISSN 2072-6694
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 14
Issue 14
Article Number 3491
DOI https://doi.org/10.3390/cancers14143491
Keywords Epigenetics; Breast cancer; TNBC; CBX2; Polycomb; PRC1; mTORC1; RBL2
Public URL https://hull-repository.worktribe.com/output/4064842

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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0

Copyright Statement
Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://cre‐ ativecommons.org/licenses/by/4.0/)



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