Inhibition of C-terminal binding protein attenuates transcription factor 4 signaling to selectively target colon cancer stem cells

Patel, Jagrut; Baranwal, Somesh; Love, Ian M.; Patel, Nirmita J.; Grossman, Steven R.; Patel, Bhaumik B.

doi:10.4161/15384101.2014.958407

Cited by 30 publications

(30 citation statements)

References 47 publications

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“…Biochemically, CtBPs directly interact with transcriptional repressors such as HDAC1 (histone deacetylase 1) and HDAC2 or transcriptional activators such as p300 and CBP through a conserved PXDLS motif (where X represents any amino acid) [20]. These repressors and activators are then recruited by TFs such as KLF3 (Kruppel-like factor 3) [21], KLF8 [22], Runx2 (RUNX family transcription factor 2) [23], and TCF4 (Transcription factor 4) [24]. Although CtBP1 and CtBP2 share over 80% identity in their protein sequences, they do not show significant redundancy in their functions [20].…”

Section: Ivyspringmentioning

confidence: 99%

Transforming growth factor beta (TGF-β) is activated by the CtBP2-p300-AP1 transcriptional complex in chronic renal failure

Zhou¹,

Wan²,

Zou³

et al. 2020

Int. J. Biol. Sci.

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Chronic renal failure (CRF), also known as chronic kidney disease (CKD), is a common renal disorder characterized by gradual kidney dysfunction. Molecular dissection reveals that transforming growth factor beta (TGF-β) plays a central role in the pathogenesis of CRF. However, the mechanism underlying TGF-β upregulation has not been demonstrated. Here, we verified that the elevated level of TGF-β was associated with the severity of CRF stages and the activation of TGF-β-mediated signaling in 120 renal biopsies from CRF patients. By analyzing the promoter region of the TGFB1 gene, we identified one AP-1 (activator protein 1) and four NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) binding sites. Knockdown of two AP-1 subunits (c-Jun and c-FOS) or blockage of AP-1 signaling with two inhibitors T-5224 and SR11302 could cause the downregulation of TGFB1, whereas knockdown of two NF-κB subunits (p65 and p50) or blockage of NF-κB signaling with two inhibitors TPCA1 and BOT-64 could not change the expression of TGFB1. Using mass spectrometry and coimmunoprecipitation analyses, we found that both c-Jun and c-FOS formed a complex with CtBP2 (C-terminal binding protein 2) and histone acetyltransferase p300. Our in vitro data demonstrated that induction of CtBP2 by recombinant IL-1β (interleukin-1 beta) led to the upregulation of TGFB1 and the activation of TGF-β downstream signaling, while knockdown of CtBP2 resulted in the reversed effects. Using chromatin immunoprecipitation assays, we revealed that the CtBP2-p300-AP1 complex specifically bound to the promoter of TGFB and that knockdown or blockage of CtBP2 significantly decreased the occupancies of the p300 and AP-1 subunits. Our results support a model in which the CtBP2-p300-AP1 transcriptional complex activates the expression of TGFB1, increasing its production and extracellular secretion. The secreted TGF-β binds to its receptors and initiates downstream signaling.

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Section: Ivyspringmentioning

confidence: 99%

Transforming growth factor beta (TGF-β) is activated by the CtBP2-p300-AP1 transcriptional complex in chronic renal failure

Zhou¹,

Wan²,

Zou³

et al. 2020

Int. J. Biol. Sci.

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“…For instance, CtBP2 has been shown to directly activate the expression levels of Tiam1 in a NADH-dependent manner (48), as well as activate the Transcription factor 4 (TCF-4) signaling pathway (49). In human multidrug resistance (MDR) cancer cell lines, CtBP1 has been shown to directly activate the expression of the MDR1 gene, thereby increasing the levels of the P-glycoprotein and drug resistance (50).…”

Section: Structural and Functional Analyses Of Ctbpmentioning

confidence: 99%

The Role of CtBP1 in Oncogenic Processes and Its Potential as a Therapeutic Target

Blevins

Huang

Zhao

2017

Molecular Cancer Therapeutics

109

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Transcriptional co-repressor proteins have emerged as an important facet of cancer etiology. These co-repressor proteins are often altered by loss- or gain-of-function mutations, leading to transcriptional imbalance. Thus, research directed at expanding our present understanding of transcriptional co-repressors could impact the future development of new cancer diagnostics, prognostics, and therapies. In this review, our current understanding of the CtBP co-repressors, and their role in both development and disease, is discussed in detail. Importantly, the role of CtBP1 overexpression in adult tissues in promoting the progression of multiple cancer types through their ability to modulate the transcription of developmental genes ectopically is explored. CtBP1 overexpression is known to be pro-tumorigenic and affects the regulation of gene networks associated with “cancer hallmarks” and malignant behavior including: increased cell survival, proliferation, migration, invasion, and the epithelial-mesenchymal transition (EMT). As a transcriptional regulator of broad developmental processes capable of promoting malignant growth in adult tissues, therapeutically targeting the CtBP1 co-repressor has the potential to be an effective method for the treatment of diverse tumor types. While efforts to develop CtBP1 inhibitors are still in the early stages, the current progress and the future perspectives of therapeutically targeting this transcriptional co-repressor are also discussed.

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“…Numerous studies have also implicated TCF4 in cancer progression. Jagrut et al reported that TCF4 signaling was upregulated in colon cancer stem cells and promoted growth and self-renewal [28]. The expression of TCF4 is associated with breast cancer chemoresistance [29].…”

Section: Discussionmentioning

confidence: 99%

Upregulation of RBM24 Exacerbates Bladder Cancer Progression by Formatting Runx1t1/TCF4/miR-625-5p Feedback Loop

Yin

Liu

et al. 2020

Preprint

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Background: RNA-binding motif protein 24 (RBM24) acts as a multifunctional determinant of cell fate, proliferation, apoptosis, and differentiation during development through regulation of pre-mRNA splicing and mRNA stability. It is also implicated in carcinogenesis, but the functions of RBM24 in bladder cancer (BC) remains unclear.Methods: Cell viability was examined by colony forming and MTT assays. Real-time quantitative PCR (RT-qPCR) and western blot analysis were used to detect the protein and mRNA levels. Co-immunoprecipitation (CoIP) and proximity ligation assay (PLA) were used to determine the protein-protein interaction. Chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), and oligo pull-down assays were used to verify DNA/RNA–protein interactions. Luciferase assay analysis was used to detect effects on transcription factor activity.Results: In the present study, we revealed that RBM24 was upregulated in BC tissues. Importantly, we found that higher level of RBM24 was correlated with poor prognosis in BC patients. Overexpression of RBM24 promoted while depletion of RBM24 inhibited BC cell proliferation in vivo and in vitro. Mechanically, RBM24 positively regulated Runx1t1 expression in BC cells by binding to and enhancing Runx1t1 mRNA stability. Runx1t1 in turn promoted RBM24 expression by interacting with TCF4. Furthermore, Runx1t1 in turn promoted RBM24 expression by interacting with the transcription factor TCF4 and depressing transcription of miR-625-5p, which directly targets and normally suppresses RBM24 expression. RBM24-regulated BC cells proliferation was moderated via the Runx1t1/TCF4/miR-625-5p feedback loop.Conclusions: In summary, these results indicate that a RBM24/Runx1t1/TCF4/miR-625-5p positive feedback loop plays a key role in BC oncogenesis. Disruption of this pathway may be a potential therapeutic strategy for BC treatment.

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Inhibition of C-terminal binding protein attenuates transcription factor 4 signaling to selectively target colon cancer stem cells

Cited by 30 publications

References 47 publications

Transforming growth factor beta (TGF-β) is activated by the CtBP2-p300-AP1 transcriptional complex in chronic renal failure

Transforming growth factor beta (TGF-β) is activated by the CtBP2-p300-AP1 transcriptional complex in chronic renal failure

The Role of CtBP1 in Oncogenic Processes and Its Potential as a Therapeutic Target

Upregulation of RBM24 Exacerbates Bladder Cancer Progression by Formatting Runx1t1/TCF4/miR-625-5p Feedback Loop

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