Twist transcription factor

Twist-related protein 1 (TWIST1) also known as class A basic helix-loop-helix protein 38 (bHLHa38) is a is_associated_with::basic helix-loop-helix is_associated_with::transcription factor that in humans is encoded by the TWIST1 is_associated_with::gene.

Function
Basic helix-loop-helix (bHLH) transcription factors have been implicated in cell lineage determination and differentiation. The protein encoded by this gene is a bHLH transcription factor and shares similarity with another bHLH transcription factor, Dermo1 (a.k.a. is_associated_with::TWIST2). The strongest expression of this mRNA is in placental tissue; in adults, mesodermally derived tissues express this mRNA preferentially.

Twist1 is thought to regulate is_associated_with::osteogenic lineage.

Clinical significance
Mutations in the TWIST1 gene are associated with is_associated_with::Saethre-Chotzen syndrome, is_associated_with::breast cancer, and is_associated_with::Sézary Syndrome.

As an oncogene
Twist plays an essential role in cancer metastasis. Over-expression of Twist or is_associated_with::methylation of its promoter is common in is_associated_with::metastatic carcinomas. Hence targeting Twist has a great promise as a cancer therapeutic. In cooperation with is_associated_with::N-Myc, Twist-1 acts as an is_associated_with::oncogene in several cancers including is_associated_with::neuroblastoma.

Twist is activated by a variety of is_associated_with::signal transduction pathways, including Akt, signal transducer and activator of transcription 3 (is_associated_with::STAT3), mitogen-activated protein kinase, Ras, and Wnt signaling. Activated Twist upregulates is_associated_with::N-cadherin and downregulates is_associated_with::E-cadherin, which are the hallmarks of EMT. Moreover, Twist plays an important role in some physiological processes involved in metastasis, like angiogenesis, invadopodia, extravasation, and chromosomal instability. Twist also protects cancer cells from apoptotic cell death. In addition, Twist is responsible for the maintenance of cancer stem cells and the development of chemotherapy resistance. Twist1 is extensively studied for its role in head- and neck cancers. Here, Twist1 has been shown to be involved in evading apoptosis, making the tumour cells resistant against chemotherapeutic drugs like cisplatin. Moreover, Twist1 has been shown to be expressed under conditions of hypoxia, corresponding to the observation that hypoxic cells respond less to chemotherapeutic drugs.

Another process in which Twist 1 is involved is tumour metastasis. The underlying mechanism is not completely understood, but it has been implicated in the upregulation of is_associated_with::matrix metalloproteinases and inhibition of is_associated_with::TIMP.

Recently, targeting Twist has gained interest as a target for cancer therapeutics. The inactivation of Twist by is_associated_with::small interfering RNA or is_associated_with::chemotherapeutic approach has been demonstrated in vitro. Moreover, several inhibitors which are antagonistic to the upstream or downstream molecules of Twist signaling pathways have also been identified. For example, thymoquinone, a natural product downregulates TWIST1 transcription factor to reduce epithelial to mesenchymal transition, and thus inhibits cancer metastasis in cancer cell lines and xenograft model of breast cancer in mouse

Interactions
Twist transcription factor has been shown to interact with is_associated_with::EP300, is_associated_with::TCF3 and is_associated_with::PCAF.