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

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.

Prognostic hub gene CBX2 drives a cancer stem cell-like phenotype in HCC revealed by multi-omics and multi-cohorts

“…A CBX2 knockout prevented CCND2 expression, and CBX2 showed a negative correlation with CDKN1A , which encodes p21 ( Figure 4I ). This supported CBX2 could pose competition to the DREAM complex [ 29 ]. On particular mechanisms, though, more study is required.…”

Multi-Omics Data Analysis Identifies Prognostic Biomarkers across Cancers

“…There are various studies about the function of CBX2 in breast cancer. Bilton et al [ 63 ] identified novel mechanisms by which CBX2 promotes breast cancer growth, and inhibition of CBX2 could be a novel therapeutic strategy. Zheng et al [ 64 ] stated that there was a positive correlation between high CBX2 expression and activation of the PI3K/AKT pathway, and that CBX2 could be a potential prognostic biomarker.…”

Integrated bioinformatics investigation and experimental validation reveals the clinical and biological significance of chromobox family in breast cancer

“…CBX2, as a component of cPRC1, participates in the epigenetic control of gene expression, leading to chromatin compaction and the suppression of speci c genes [28]. Recent research revealed that CBX2 enhances mTORC1 activity by suppressing mTORC1 inhibitors, and inhibiting CBX2 might reduce TNBC cell growth and viability by inhibiting mTORC1 downstream [29]. Another study demonstrated that silencing CBX2 affected numerous oncogenes in the MAPK signaling pathway in acute myeloid leukemia [30].…”