Transcription Factor Drug Targets

Papavassiliou, Kostas A.; Papavassiliou, Athanasios G.

doi:10.1002/jcb.25605

Cited by 103 publications

(74 citation statements)

References 48 publications

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“…17,18 Transcription factors are protein molecules that can specifically bind to upstream of the 5ʹ end of the gene, thereby ensuring target gene expression with a specific intensity. 19 TCF1 is expressed in multiple isoforms. All isoforms of TCF1 share the common HDAC and DNA binding domains.…”

Section: Introductionmentioning

confidence: 99%

<p>Progression of Thyroid Carcinoma Is Promoted by the m6A Methyltransferase METTL3 Through Regulating m6A Methylation on TCF1</p>

Wang¹,

Jiang²,

Zhang³

et al. 2020

OTT

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Objective: This study aims to uncover the progression of thyroid carcinoma influenced by the m6A methyltransferase METTL3 through regulating m 6 A methylation on TCF1 mRNA and the activated Wnt pathway. Methods: Thyroid carcinoma tissues and paracancerous ones were collected for detecting levels of METTL3 and TCF1. Potential correlation between levels of METTL3 and TCF1 was analyzed by Pearson analysis. Survival of thyroid carcinoma patients influenced by METTL3 level was assessed by Kaplan-Meier method. Regulatory effect of METTL3 on migratory ability in TPC-1 cells was examined by wound healing assay. The interaction between METTL3 with TCF1 and IGF2BP2 was verified by RNA-Binding Protein Immunoprecipitation (RIP) assay. Meanwhile, the activity of the Wnt pathway was reflected by TOP/FOP-Flash. At last, rescue experiments were conducted to clarify the involvement of TCF1 in phenotype changes of thyroid carcinoma cells that were regulated by METTL3. Results: METTL3 and TCF1 were upregulated in thyroid carcinoma. Similarly, METTL3 was highly expressed in thyroid carcinoma cells as well. Kaplan-Meier method uncovered poor prognosis in thyroid carcinoma patients expressing a high level of METTL3. Silence of METTL3 inhibited migratory ability and Wnt activity in TPC-1 cells. RIP assay confirmed the interaction between TCF1 and METTL3 or IGF2BP2. Moreover, METTL3 positively regulated the enrichment abundance of TCF1 in anti-IGF2BP2. Rescue experiments demonstrated that TCF1 was responsible for METTL3-regulated thyroid carcinoma progression via the m 6 A methylation. Conclusion: Upregulated m6A methyltransferase METTL3 promotes the progression of thyroid carcinoma through m 6 A methylation on TCF1.

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Section: Introductionmentioning

confidence: 99%

<p>Progression of Thyroid Carcinoma Is Promoted by the m6A Methyltransferase METTL3 Through Regulating m6A Methylation on TCF1</p>

Wang¹,

Jiang²,

Zhang³

et al. 2020

OTT

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“…TFs represent the key point of convergence of multiple signaling pathways in cells and play critical roles in tumorigenesis and cancer progression because TFs can regulate comprehensive transcription alterations in cancer cells. [ 3–5 ] Sp4 is a general TF that binds to and acts through GC base boxes, which are frequently occurring DNA elements present in many promoters and enhancers. [ 14 ] We found that SRSP promoted the inclusion of exon 3 of TF Sp4 to promote long Sp4 splicing variant formation (we termed L‐Sp4) and suppress short Sp4 splicing variant formation without exon 3 (we termed S‐Sp4) ( Figure A).…”

Section: Resultsmentioning

confidence: 99%

“…It has been estimated that TFs account for 20% of oncogenes in cancer. [ 3–5 ] The classic examples include p53, Ets, AP‐1, c‐Myc, and NFκB. Alternations of TF activity underlie many human diseases including cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Many oncogenic signaling pathways alter the functions of TFs to implement gene expression changes, thereby driving tumorigenesis and cancer progression. [ 4,5 ] The deregulation of TFs by modifications (such as phosphorylation), sublocalization, stabilization, binding, and transactivation is linked to tumorigenesis and cancer progression. [ 4,5 ] RNA alternative splicing (AS) is an essential process that yields structurally and functionally distinct mRNA and protein variants to expand the functional and regulatory capacity of metazoan genomes.…”

Section: Introductionmentioning

confidence: 99%

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Small Protein Hidden in lncRNA LOC90024 Promotes “Cancerous” RNA Splicing and Tumorigenesis

Meng

Chen

et al. 2020

Advanced Science

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Conventional therapies for late‐stage colorectal cancer (CRC) have limited effects because of chemoresistance, recurrence, and metastasis. The “hidden” proteins/peptides encoded by long noncoding RNAs (lncRNAs) may be a novel resource bank for therapeutic options for patients with cancer. Here, lncRNA LOC90024 is discovered to encode a small 130‐amino acid protein that interacts with several splicing regulators, such as serine‐ and arginine‐rich splicing factor 3 (SRSF3), to regulate mRNA splicing, and the protein thus is named “Splicing Regulatory Small Protein” (SRSP). SRSP, but not LOC90024 lncRNA itself, promotes CRC tumorigenesis and progression, while silencing of SRSP suppresses CRC tumorigenesis. Mechanistically, SRSP increases the binding of SRSF3 to exon 3 of transcription factor Sp4, resulting in the inclusion of Sp4 exon 3 to induce the formation of the “cancerous” long Sp4 isoform (L‐Sp4 protein) and inhibit the formation of the “noncancerous” short Sp4 isoform (S‐Sp4 peptide), which lacks the transactivation domain. The upregulated SRSP level is positively associated with malignant phenotypes and poor prognosis in patients with CRC. Collectively, the findings uncover that a lncRNA‐encoded small protein SRSP induces “cancerous” Sp4 splicing variant formation and may be a potential prognostic biomarker and therapeutic target for patients with CRC.

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“…Because transcription factors play central roles in the cell, mutations in these proteins can lead to aberrant gene regulation, which in turn, can lead to development of diseases [recently reviewed in Ref. ( ). Many transcription factors regulate cell survival and proliferation, and their dysregulation is often key to oncogenesis: for example, the MYC transcription factor is involved in numerous normal cellular processes, but in deregulated and overexpressed form, MYC is involved in over half of all human cancers [see Ref.…”

Section: Introductionmentioning

confidence: 99%

Peptide therapeutics that directly target transcription factors

Inamoto

Shin

2018

Peptide Science

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Transcription factors regulate gene expression in cells and control cellular development, function, and death. Dysregulation of transcription factors is often associated with disease, including cancer. As such, transcription factors are attractive targets for design of therapeutics against disease. Transcription factors function using protein‐protein and protein‐DNA interactions that occur over relatively large surface areas: this lack of a small and defined “ligand binding site” has proven to be challenging to target with small molecules. Peptide therapeutics, therefore, provide an alternate approach toward design of inhibitory agents. Transcription factors are conveniently modular by design: just the small domain that is responsible for the transcription factor's DNA binding or a protein‐protein interaction or another function, can serve as the basis for novel peptide therapeutics. In this review, examples of peptides that directly interfere with transcription factors will be discussed.

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Transcription Factor Drug Targets

Cited by 103 publications

References 48 publications

<p>Progression of Thyroid Carcinoma Is Promoted by the m6A Methyltransferase METTL3 Through Regulating m6A Methylation on TCF1</p>

<p>Progression of Thyroid Carcinoma Is Promoted by the m6A Methyltransferase METTL3 Through Regulating m6A Methylation on TCF1</p>

Small Protein Hidden in lncRNA LOC90024 Promotes “Cancerous” RNA Splicing and Tumorigenesis

Peptide therapeutics that directly target transcription factors

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