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

McIntyre, Alexander J; Angel, Charlotte Zoe; Smith, J. S.; Templeman, Amy; Beattie, Katherine; Beattie, S.; Ormrod, Alice; Devlin, Eadaoin; McGreevy, Charles; Bothwell, Chloe; Eddie, Sharon L.; Buckley, Niamh E.; Mullan, Paul B.

doi:10.1093/nar/gkac494

Cited by 5 publications

(9 citation statements)

References 53 publications

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“…While we did test two direct DNA-binding proteins-GFI1 and HMG20B-other repressive components, like Phf21b, INSM1, Pax2, TBX2, and SNAI2, have been reported as KDM1A partners in different tissues and might contribute to NDRG1 repression as well. [36][37][38][39][40] Although NDRG1 has been initially characterized as a tumor suppressor, its roles seem to be highly contextual, such that in certain tissues it may even exhibit tumor promoting effects. [41,42] Our transcriptome analysis showed that NDRG1 upregulation induced an inhibition of Wnt signaling that was accompanied by a marked reduction of cycling cells.…”

Section: Discussionmentioning

confidence: 99%

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CRISPR/Cas9 Screen in Gastric Cancer Patient‐Derived Organoids Reveals KDM1A‐NDRG1 Axis as a Targetable Vulnerability

et al. 2023

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Viability CRISPR screens have proven indispensable in parsing genome function. However, their application in new, more physiologically relevant culturing systems like patient-derived organoids (PDOs) has been much slower. To probe epigenetic contribution to gastric cancer (GC), the third leading cause of cancer-related deaths worldwide, the first negative selection CRISPR screen in GC PDOs that faithfully preserve primary tumor characteristics is performed. Extensive quality control measurements showing feasibility of CRISPR screens in primary organoid culture are provided. The screen reveals the histone lysine demethylase-1A (KDM1A) to constitute a GC vulnerability. Both genetic and pharmacological inhibition of KDM1A cause organoid growth retardation. Further, it is shown that most of KDM1A cancer-supporting functions center on repression of N-myc downstream regulates gene-1 (NDRG1). De-repression of NDRG1 by KDM1A inhibitors (KDM1Ai) causes inhibition of Wnt signaling and a strong G1 cell cycle arrest. Finally, by profiling 20 GC PDOs, it is shown that NDRG1 upregulation predicts KDM1Ai response with 100% sensitivity and 82% specificity in the tested cohort. Thus, this work pioneers the use of negative selection CRISPR screens in patient-derived organoids, identifies a marker of KDM1Ai response, and accordingly a cohort of patients who may benefit from such therapy.

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Section: Discussionmentioning

confidence: 99%

“…While we did test two direct DNA‐binding proteins—GFI1 and HMG20B—other repressive components, like Phf21b, INSM1, Pax2, TBX2, and SNAI2, have been reported as KDM1A partners in different tissues and might contribute to NDRG1 repression as well. [ 36–40 ]…”

Section: Discussionmentioning

confidence: 99%

CRISPR/Cas9 Screen in Gastric Cancer Patient‐Derived Organoids Reveals KDM1A‐NDRG1 Axis as a Targetable Vulnerability

et al. 2023

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“…Having identified GR as a novel interactor of TBX2 in CRPC, we next sought to investigate the possibility of pharmacologically targeting the TBX2-GR interaction. Previous studies have identified an interaction between TBX2 and LSD1 as a part of the COREST complex 17 . These reports also identified that the interaction between TBX2 and LSD1 could be pharmacologically targeted through the LSD1 inhibitor SP2509 17 , and that disruption of the TBX2-LSD1 interaction resulted in the inhibition of TBX2 downstream targets 17 .…”

Section: Sp-2509 An Allosteric Lsd1 Inhibitor Impedes Tbx2-gr Physica...mentioning

confidence: 98%

“…Previous studies have identified an interaction between TBX2 and LSD1 as a part of the COREST complex 17 . These reports also identified that the interaction between TBX2 and LSD1 could be pharmacologically targeted through the LSD1 inhibitor SP2509 17 , and that disruption of the TBX2-LSD1 interaction resulted in the inhibition of TBX2 downstream targets 17 . Further, and of relevance to our study, another report showed that LSD1 is upregulated in CRPC 44,45 .…”

Section: Sp-2509 An Allosteric Lsd1 Inhibitor Impedes Tbx2-gr Physica...mentioning

confidence: 98%

TBX2 driven switch from Androgen Receptor to Glucocorticoid Receptor signaling confers therapeutic resistance in Prostate Cancer

Dutta

Patel

Khedmatgozar

et al. 2023

Preprint

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Recent studies have highlighted that androgen receptor (AR) signaling can be bypassed via activation of the glucocorticoid receptor (GR), and that this bypass drives enzalutamide resistance in advanced prostate cancer (PCa). However, the molecular mechanism(s) that drive the switch from AR to GR signaling remain unknown. We have previously reported that TBX2, a developmental T-box transcription factor (TF), is over-expressed in castrate resistant prostate cancer (CRPC) and that TBX2 drives the CRPC phenotype via cell-intrinsic and exosome-mediated paracrine modes. Our current study demonstrates that TBX2, a TF with known repressor and activator functions, may be the molecular switch that represses AR on one hand while activating GR expression on the other to drive CRPC. Mechanistically, our studies revealed a two-tiered mechanism of AR repression by TBX2 wherein TBX2 directly binds to the promoters of AR and GATA2, an AR coregulator, thereby resulting in the repression of AR as well as GATA2. Conversely, our results demonstrate that TBX2 mediates increased expression of GR via directly binding to the GR promoter, and through TBX2-GR functional protein-protein interaction. Our results demonstrate that the TBX2 driven switch from AR to GR signaling results in enzalutamide resistance since GR inhibition in the context of TBX2 over-expression attenuates enzalutamide resistance. Further, we present evidence that SP2509 based allosteric inhibition of Lysine Specific Demethylase 1 (LSD1), a protein that interacts with TBX2 as part of the Co-repressor of RE1-Silencing Transcription Factor (COREST) complex, is able to disrupt TBX2-GR interaction. Taken together, our study has identified TBX2 as the molecular switch that drives AR to GR signaling and thereby confers enzalutamide resistance in CRPC. Furthermore, our study provides key insights into a potential therapeutic strategy of targeting the AR to GR switch wherein SP2509-based allosteric inhibition of TBX2-LSD1 could be harnessed to target the TBX2-GR interaction, thereby resulting in the inhibition of enzalutamide resistance in CRPC.

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“…ZNF217 negatively regulates the expression of EPB41L4A-AS2 at the transcriptional level, most probably through the enhanced recruitment of EZH2 and increased H3K27me3 enrichment at EPB41L4A-AS2 locus [ 67 ]. A recent study identified a new tumor-suppressive lncRNA, namely LINC00111, whose transcription is negatively regulated by the TXB2 transcriptional complex [ 106 ]. In BCa cells, ZNF217 was identified to be a novel interactor of TBX2 that binds to 30% of TXB2-bound promoters, including that of the lncRNA LINC00111.…”

Section: Noncoding Rna Network Target Znf217 Mrna ...mentioning

confidence: 99%

The Intricate Interplay between the ZNF217 Oncogene and Epigenetic Processes Shapes Tumor Progression

Fahmé

Ramadan

et al. 2022

Cancers

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The oncogenic transcription factor ZNF217 orchestrates several molecular signaling networks to reprogram integrated circuits governing hallmark capabilities within cancer cells. High levels of ZNF217 expression provide advantages to a specific subset of cancer cells to reprogram tumor progression, drug resistance and cancer cell plasticity. ZNF217 expression level, thus, provides a powerful biomarker of poor prognosis and a predictive biomarker for anticancer therapies. Cancer epigenetic mechanisms are well known to support the acquisition of hallmark characteristics during oncogenesis. However, the complex interactions between ZNF217 and epigenetic processes have been poorly appreciated. Deregulated DNA methylation status at ZNF217 locus or an intricate cross-talk between ZNF217 and noncoding RNA networks could explain aberrant ZNF217 expression levels in a cancer cell context. On the other hand, the ZNF217 protein controls gene expression signatures and molecular signaling for tumor progression by tuning DNA methylation status at key promoters by interfering with noncoding RNAs or by refining the epitranscriptome. Altogether, this review focuses on the recent advances in the understanding of ZNF217 collaboration with epigenetics processes to orchestrate oncogenesis. We also discuss the exciting burgeoning translational medicine and candidate therapeutic strategies emerging from those recent findings connecting ZNF217 to epigenetic deregulation in cancer.

show abstract

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

Cited by 5 publications

References 53 publications

CRISPR/Cas9 Screen in Gastric Cancer Patient‐Derived Organoids Reveals KDM1A‐NDRG1 Axis as a Targetable Vulnerability

CRISPR/Cas9 Screen in Gastric Cancer Patient‐Derived Organoids Reveals KDM1A‐NDRG1 Axis as a Targetable Vulnerability

TBX2 driven switch from Androgen Receptor to Glucocorticoid Receptor signaling confers therapeutic resistance in Prostate Cancer

The Intricate Interplay between the ZNF217 Oncogene and Epigenetic Processes Shapes Tumor Progression

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