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Identification of targets of Twist1 transcription factor in thyroid cancer cells
Gennaro Di Maro1, Francesca Maria Orlandella, Tammaro Claudio Bencivenga
1Dipartimento di Medicina Molecolare e Biotecnologie Mediche (G.D.M., F.M.O., T.C.B., P.S.), Università di Napoli "Federico II," Italy 80131; Dipartimento di Area Medica (C.U.), Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy 56126; Dipartimento di Patologia Chirugica, Medica (F.B.), Molecolare e dell'Area Critica dell' Università di Pisa, Italy 56124; Experimental Oncology 1 (R.M.), Centro di Riferimento Oncologico, Aviano, Italy 33081; and Dipartimento di Scienze Motorie e del Benessere (G.S.), Universita' "Parthenope," 80133 Napoli, Italy 80133.
Context:
Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human tumors. Twist1 is a basic helix-loop-helix transcription factor involved in cancer development and progression. We showed that Twist1 affects thyroid cancer cell survival and motility.
Objective:
We aimed to identify Twist1 targets in thyroid cancer cells.
Design:
Transcriptional targets of Twist1 were identified by gene expression profiling the TPC-Twist1 cells in comparison with control cells. Functional studies were performed by silencing in TPC-Twist1 and in CAL62 cells the top 10 upregulated genes and by evaluating cell proliferation, survival, migration, and invasion. Chromatin immunoprecipitation was performed to verify direct binding of Twist1 to target genes. Quantitative RT-PCR was applied to study the expression level of Twist1 target genes in human thyroid carcinoma samples.
Results:
According to the gene expression profile, the top functions enriched in TPC-Twist1 cells were cellular movement, cellular growth and proliferation, and cell death and survival. Silencing of the top 10 upregulated genes reduced viability of TPC-Twist1 and of CAL62 cells. Silencing of COL1A1, KRT7, and PDZK1 also induced cell death. Silencing of HS6ST2, THRB, ID4, RHOB, and PDZK1IP also impaired migration and invasion of TPC-Twist1 and of CAL62 cells. Chromatin immunoprecipitation showed that Twist1 directly binds the promoter of the top 10 upregulated genes. Quantitative RT-PCR showed that HS6ST2, COL1A1, F2RL1, LEPREL1, PDZK1, and PDZK1IP1 are overexpressed in thyroid carcinoma samples compared with normal thyroids.
Conclusions:
We identified a set of genes that mediates Twist1 biological effects in thyroid cancer cells.
Insights
This study identifies genes regulated by Twist1, a factor in aggressive anaplastic thyroid carcinoma (ATC). These identified Twist1 targets are crucial for thyroid cancer cell survival, proliferation, and metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Anaplastic thyroid carcinoma (ATC) is a highly aggressive human tumor.
- Twist1, a transcription factor, is implicated in cancer development and progression, affecting thyroid cancer cell survival and motility.
Purpose of the Study:
- To identify transcriptional targets of Twist1 in thyroid cancer cells.
- To elucidate the role of Twist1-regulated genes in thyroid cancer progression.
Main Methods:
- Gene expression profiling to identify Twist1 targets.
- Functional studies involving gene silencing to assess effects on cell viability, proliferation, migration, and invasion.
- Chromatin immunoprecipitation to confirm direct Twist1 binding to target gene promoters.
- Quantitative RT-PCR to analyze target gene expression in human thyroid carcinoma samples.
Main Results:
- Gene expression profiling revealed Twist1-upregulated genes are involved in cellular movement, growth, proliferation, and survival.
- Silencing of top Twist1 targets reduced cancer cell viability, induced cell death, and impaired migration and invasion.
- Twist1 was confirmed to directly bind the promoters of these target genes.
- Several genes, including HS6ST2, COL1A1, and PDZK1, were found to be overexpressed in thyroid carcinoma tissues.
Conclusions:
- A set of genes mediating Twist1's biological effects in thyroid cancer has been identified.
- These findings provide insights into the molecular mechanisms driving anaplastic thyroid carcinoma progression.
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