TBX2 interacts with Heterochromatin Protein 1 to recruit a novel repression complex to EGR1-responsive promoters and promote the proliferation of breast cancer cells


Session type:

Alexander McIntyre1,Nyree Crawford1,Anna McCormick1,Zenobia D'Costa1,Naomi Dickson1,Niamh Buckley1,Paul Mullan1



TBX2 (T-Box2) is an oncogenic transcription factor whose genomic locus is amplified in approximately 10% of breast cancers leading to TBX2 overexpression and poor clinical outcome. We have shown previously that TBX2 interacts with the stress response transcription factor Early Growth Response 1 (EGR1) to co-repress EGR1 target genes such as the breast tumour suppressor NDRG1. Here we show the mechanistic basis of this TBX2 repression complex.


TBX2-amplified MCF-7 and BT-474 cell lines were utilised in this study. A number of molecular (Western blot, PCR, IP, luciferase reporter, ChIP) and phenotypic (proliferation, colony-forming) assays were applied to characterise the mechanism of gene repression and to investigate the importance of the TBX2 complex in promoting cellular growth and survival.


We show that TBX2 interacts with Heterochromatin Protein 1γ (HP1γ) and the corepressor protein KAP1 to repress EGR1 target genes and maintain proliferation of breast cancer cells. TBX2 interacts with HP1γ through a conserved HP1-binding motif, which is also essential for the TBX2-KAP1 interaction. TBX2, KAP1 and HP1γ establish a repressive H3K9me3 mark around the NDRG1 proximal promoter coincident with recruitment of a histone methyltransferase complex containing G9A, Enhancer of Zeste 2 (EZH2) and Suppressor of Zeste 12 (SUZ12). Knockdown of G9A, EZH2 or SUZ12 resulted in upregulation of TBX2/EGR1 co-regulated targets accompanied by a dramatic inhibition of cell proliferation. Finally, we show that a chemical inhibitor (BIX-01294) targeting G9A methyltransferase activity enhances NDRG1 expression, downregulates anti-senescence proteins and synergises with TBX2 inhibition to abrogate cellular survival.


Taken together these data demonstrate that TBX2 promotes suppression of normal growth control mechanisms through recruitment of a multicomponent repression complex to EGR1-responsive promoters, leading to the uncontrolled proliferation of cancer cells. The disruption of this repression complex through use of selective methyltransferase inhibitors represents a potential therapeutic strategy for treatment of TBX2-dependent breast tumours.