TBX2 acts as a potent transcriptional silencer of tumour suppressor genes through interaction with the CoREST complex to sustain the proliferation of breast cancers

Author:

McIntyre Alexander J1,Angel Charlotte Z1,Smith James S2,Templeman Amy1,Beattie Katherine1,Beattie Shannon1,Ormrod Alice1ORCID,Devlin Eadaoin1,McGreevy Charles1,Bothwell Chloe1,Eddie Sharon L1,Buckley Niamh E1,Williams Rich1,Mullan Paul B1ORCID

Affiliation:

1. Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast , Belfast BT9 7AE, UK

2. The Institute of Cancer Research , 15 Cotswold Road, Sutton, London SM2 5NG, UK

Abstract

Abstract Chromosome 17q23 amplification occurs in 20% of primary breast tumours and is associated with poor outcome. The TBX2 gene is located on 17q23 and is often over-expressed in this breast tumour subset. TBX2 is an anti-senescence gene, promoting cell growth and survival through repression of Tumour Suppressor Genes (TSGs), such as NDRG1 and CST6. Previously we found that TBX2 cooperates with the PRC2 complex to repress several TSGs, and that PRC2 inhibition restored NDRG1 expression to impede cellular proliferation. Here, we now identify CoREST proteins, LSD1 and ZNF217, as novel interactors of TBX2. Genetic or pharmacological targeting of CoREST emulated TBX2 loss, inducing NDRG1 expression and abolishing breast cancer growth in vitro and in vivo. Furthermore, we uncover that TBX2/CoREST targeting of NDRG1 is achieved by recruitment of TBX2 to the NDRG1 promoter by Sp1, the abolishment of which resulted in NDRG1 upregulation and diminished cancer cell proliferation. Through ChIP-seq we reveal that 30% of TBX2-bound promoters are shared with ZNF217 and identify novel targets repressed by TBX2/CoREST; of these targets a lncRNA, LINC00111, behaves as a negative regulator of cell proliferation. Overall, these data indicate that inhibition of CoREST proteins represents a promising therapeutic intervention for TBX2-addicted breast tumours.

Funder

Breast Cancer Campaign/Breast Cancer Now

Breast Cancer Ireland

Publisher

Oxford University Press (OUP)

Subject

Genetics

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