Twist-related protein 1 explained

Twist-related protein 1 (TWIST1) also known as class A basic helix–loop–helix protein 38 (bHLHa38) is a basic helix-loop-helix transcription factor that in humans is encoded by the TWIST1 gene.^{[1] [2]}

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. TWIST2). The strongest expression of this mRNA is in placental tissue; in adults, mesodermally derived tissues express this mRNA preferentially.^[3]

Twist1 is thought to regulate osteogenic lineage.^[4]

Clinical significance

Mutations in the TWIST1 gene are associated with Saethre–Chotzen syndrome,^{[5] [6]} breast cancer,^[7] and Sézary syndrome.^[8]

Craniosynostosis

TWIST1 mutations are involved in a number of craniosynostosis presentations. It can present in nonsyndromic forms (isolated scaphocephaly, right unicoronal synostosis, and turricephaly), but also in syndromic forms such as:^[9]

• Acrocephalosyndactyly type 1 (Apert syndrome) (primary FGFR2)
• Beare-Stevenson cutis gyrata syndrome (primary FGFR2)
• Crouzon syndrome (primary FGFR2)
• Crouzon syndrome-acanthosis nigricans syndrome (primary FGFR3)
• Jackson-Weiss syndrome (primary FGFR1 or FGFR2)
• Muenke syndrome (primary FGFR3)
• Pfeiffer syndrome (primary FGFR1 or FGFR2)

As an oncogene

Twist plays an essential role in cancer metastasis. Over-expression of Twist or methylation of its promoter is common in metastatic carcinomas. Hence targeting Twist has a great promise as a cancer therapeutic.^[10] In cooperation with N-Myc, Twist-1 acts as an oncogene in several cancers including neuroblastoma.^{[7] [11]}

Twist is activated by a variety of signal transduction pathways, including Akt, signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase, Ras, and Wnt signaling. Activated Twist upregulates N-cadherin and downregulates 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.^{[10] [12]} Twist1 is extensively studied for its role in head- and neck cancers.^[13] Here and in epithelial ovarian cancer, Twist1 has been shown to be involved in evading apoptosis, making the tumour cells resistant against platinum-based chemotherapeutic drugs like cisplatin.^[14] Moreover, Twist1 has been shown to be expressed under conditions of hypoxia, corresponding to the observation that hypoxic cells respond less to chemotherapeutic drugs.^[13]

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 matrix metalloproteinases^[15] and inhibition of TIMP.^[16]

Recently, targeting Twist has gained interest as a target for cancer therapeutics. The inactivation of Twist by small interfering RNA or 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.^[10]

Interactions

Twist transcription factor has been shown to interact with EP300,^[17] TCF3^[18] and PCAF.^[17]

See also

• Transcription factor
• TWIST2

Further reading

• Seto ML, Lee SJ, Sze RW, Cunningham ML . Another TWIST on Baller-Gerold syndrome . American Journal of Medical Genetics . 104 . 4 . 323–30 . Dec 2001 . 11754069 . 10.1002/ajmg.10065 .
• Brueton LA, van Herwerden L, Chotai KA, Winter RM . The mapping of a gene for craniosynostosis: evidence for linkage of the Saethre-Chotzen syndrome to distal chromosome 7p . Journal of Medical Genetics . 29 . 10 . 681–5 . Oct 1992 . 1433226 . 1016122 . 10.1136/jmg.29.10.681 .
• Bianchi DW, Cirillo-Silengo M, Luzzatti L, Greenstein RM . Interstitial deletion of the short arm of chromosome 7 without craniosynostosis . Clinical Genetics . 19 . 6 . 456–61 . Jun 1981 . 7296937 . 10.1111/j.1399-0004.1981.tb02064.x . 25464482 .
• Rose CS, King AA, Summers D, Palmer R, Yang S, Wilkie AO, Reardon W, Malcolm S, Winter RM . Localization of the genetic locus for Saethre-Chotzen syndrome to a 6 cM region of chromosome 7 using four cases with apparently balanced translocations at 7p21.2 . Human Molecular Genetics . 3 . 8 . 1405–8 . Aug 1994 . 7987323 . 10.1093/hmg/3.8.1405 . free .
• Maw M, Kar B, Biswas J, Biswas P, Nancarrow D, Bridges R, Kumaramanickavel G, Denton M, Badrinath SS . Linkage of blepharophimosis syndrome in a large Indian pedigree to chromosome 7p . Human Molecular Genetics . 5 . 12 . 2049–54 . Dec 1996 . 8968762 . 10.1093/hmg/5.12.2049 .
• el Ghouzzi V, Le Merrer M, Perrin-Schmitt F, Lajeunie E, Benit P, Renier D, Bourgeois P, Bolcato-Bellemin AL, Munnich A, Bonaventure J . Mutations of the TWIST gene in the Saethre-Chotzen syndrome . Nature Genetics . 15 . 1 . 42–6 . Jan 1997 . 8988167 . 10.1038/ng0197-42 . 22140671 .
• Wang SM, Coljee VW, Pignolo RJ, Rotenberg MO, Cristofalo VJ, Sierra F . Cloning of the human twist gene: its expression is retained in adult mesodermally-derived tissues . Gene . 187 . 1 . 83–92 . Mar 1997 . 9073070 . 10.1016/S0378-1119(96)00727-5 .
• Krebs I, Weis I, Hudler M, Rommens JM, Roth H, Scherer SW, Tsui LC, Füchtbauer EM, Grzeschik KH, Tsuji K, Kunz J . Translocation breakpoint maps 5 kb 3' from TWIST in a patient affected with Saethre-Chotzen syndrome . Human Molecular Genetics . 6 . 7 . 1079–86 . Jul 1997 . 9215678 . 10.1093/hmg/6.7.1079 . free .
• Rose CS, Patel P, Reardon W, Malcolm S, Winter RM . The TWIST gene, although not disrupted in Saethre-Chotzen patients with apparently balanced translocations of 7p21, is mutated in familial and sporadic cases . Human Molecular Genetics . 6 . 8 . 1369–73 . Aug 1997 . 9259286 . 10.1093/hmg/6.8.1369 . free .
• Hamamori Y, Wu HY, Sartorelli V, Kedes L . The basic domain of myogenic basic helix-loop-helix (bHLH) proteins is the novel target for direct inhibition by another bHLH protein, Twist . Molecular and Cellular Biology . 17 . 11 . 6563–73 . Nov 1997 . 9343420 . 232510 . 10.1128/mcb.17.11.6563.
• Gripp KW, Stolle CA, Celle L, McDonald-McGinn DM, Whitaker LA, Zackai EH . TWIST gene mutation in a patient with radial aplasia and craniosynostosis: further evidence for heterogeneity of Baller-Gerold syndrome . American Journal of Medical Genetics . 82 . 2 . 170–6 . Jan 1999 . 9934984 . 10.1002/(SICI)1096-8628(19990115)82:2<170::AID-AJMG14>3.0.CO;2-X .
• Hamamori Y, Sartorelli V, Ogryzko V, Puri PL, Wu HY, Wang JY, Nakatani Y, Kedes L . Regulation of histone acetyltransferases p300 and PCAF by the bHLH protein twist and adenoviral oncoprotein E1A . Cell . 96 . 3 . 405–13 . Feb 1999 . 10025406 . 10.1016/S0092-8674(00)80553-X . 15808193 . free .
• Kunz J, Hudler M, Fritz B . Identification of a frameshift mutation in the gene TWIST in a family affected with Robinow-Sorauf syndrome . Journal of Medical Genetics . 36 . 8 . 650–2 . Aug 1999 . 10465122 . 1762975 . 10.1136/jmg.36.8.650 .
• Maestro R, Dei Tos AP, Hamamori Y, Krasnokutsky S, Sartorelli V, Kedes L, Doglioni C, Beach DH, Hannon GJ . Twist is a potential oncogene that inhibits apoptosis . Genes & Development . 13 . 17 . 2207–17 . Sep 1999 . 10485844 . 317004 . 10.1101/gad.13.17.2207 .
• El Ghouzzi V, Legeai-Mallet L, Aresta S, Benoist C, Munnich A, de Gunzburg J, Bonaventure J . Saethre-Chotzen mutations cause TWIST protein degradation or impaired nuclear location . Human Molecular Genetics . 9 . 5 . 813–9 . Mar 2000 . 10749989 . 10.1093/hmg/9.5.813 . free .
• Lee MS, Lowe G, Flanagan S, Kuchler K, Glackin CA . Human Dermo-1 has attributes similar to twist in early bone development . Bone . 27 . 5 . 591–602 . Nov 2000 . 11062344 . 10.1016/S8756-3282(00)00380-X .
• Dollfus H, Kumaramanickavel G, Biswas P, Stoetzel C, Quillet R, Denton M, Maw M, Perrin-Schmitt F . Identification of a new TWIST mutation (7p21) with variable eyelid manifestations supports locus homogeneity of BPES at 3q22 . Journal of Medical Genetics . 38 . 7 . 470–2 . Jul 2001 . 11474656 . 1757180 . 10.1136/jmg.38.7.470 .
• Elanko N, Sibbring JS, Metcalfe KA, Clayton-Smith J, Donnai D, Temple IK, Wall SA, Wilkie AO . A survey of TWIST for mutations in craniosynostosis reveals a variable length polyglycine tract in asymptomatic individuals . Human Mutation . 18 . 6 . 535–41 . Dec 2001 . 11748846 . 10.1002/humu.1230 . 45021510 . free .
• Nurnberg ST, Guerraty MA, Wirka RC, Rao HS, Pjanic M, Norton S, Serrano F, Perisic L, Elwyn S, Pluta J, Zhao W, Testa S, Park Y, Nguyen T, Ko YA, Wang T, Hedin U, Sinha S, Barash Y, Brown CD, Quertermous T, Rader DJ . 6 . Genomic profiling of human vascular cells identifies TWIST1 as a causal gene for common vascular diseases . PLOS Genetics . 16 . 1 . e1008538 . January 2020 . 31917787 . 6975560 . 10.1371/journal.pgen.1008538 . free .
• ZZhang J, Guo JR, Wu XL, Wang X, Zhu ZM, Wang Y, Gu X, Fan Y . TWIST1 induces phenotypic switching of vascular smooth muscle cells by downregulating p68 and microRNA-143/145 . FEBS Open Bio . 11 . 3 . 932–943 . March 2021 . 33470057 . 7931233 . 10.1002/2211-5463.13092 .

External links

• GeneReviews/NCBI.NIH.UW entry on Saethre–Chotzen syndrome

Notes and References

1. Bourgeois P, Stoetzel C, Bolcato-Bellemin AL, Mattei MG, Perrin-Schmitt F . The human H-twist gene is located at 7p21 and encodes a B-HLH protein that is 96% similar to its murine M-twist counterpart . Mammalian Genome . 7 . 12 . 915–7 . Dec 1996 . 8995765 . 10.1007/s003359900269 . 42710079 .
2. Dollfus H, Kumaramanickavel G, Biswas P, Stoetzel C, Quillet R, Denton M, Maw M, Perrin-Schmitt F . Identification of a new TWIST mutation (7p21) with variable eyelid manifestations supports locus homogeneity of BPES at 3q22 . Journal of Medical Genetics . 38 . 7 . 470–2 . Jul 2001 . 11474656 . 1757180 . 10.1136/jmg.38.7.470 .
3. Web site: Entrez Gene: TWIST1 twist homolog 1 (acrocephalosyndactyly 3; Saethre–Chotzen syndrome) (Drosophila).
4. Lee MS, Lowe GN, Strong DD, Wergedal JE, Glackin CA . TWIST, a basic helix–loop–helix transcription factor, can regulate the human osteogenic lineage . Journal of Cellular Biochemistry . 75 . 4 . 566–77 . Dec 1999 . 10572240 . 10.1002/(SICI)1097-4644(19991215)75:4<566::AID-JCB3>3.0.CO;2-0 . 21874692 .
5. Kress W, Schropp C, Lieb G, Petersen B, Büsse-Ratzka M, Kunz J, Reinhart E, Schäfer WD, Sold J, Hoppe F, Pahnke J, Trusen A, Sörensen N, Krauss J, Collmann H . Saethre-Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome . European Journal of Human Genetics . 14 . 1 . 39–48 . Jan 2006 . 16251895 . 10.1038/sj.ejhg.5201507 . free .
6. Howard TD, Paznekas WA, Green ED, Chiang LC, Ma N, Ortiz de Luna RI, Garcia Delgado C, Gonzalez-Ramos M, Kline AD, Jabs EW . Mutations in TWIST, a basic helix-loop-helix transcription factor, in Saethre-Chotzen syndrome . Nature Genetics . 15 . 1 . 36–41 . Jan 1997 . 8988166 . 10.1038/ng0197-36 . 35360537 .
7. Martin TA, Goyal A, Watkins G, Jiang WG . Expression of the transcription factors snail, slug, and twist and their clinical significance in human breast cancer . Annals of Surgical Oncology . 12 . 6 . 488–96 . Jun 2005 . 15864483 . 10.1245/ASO.2005.04.010 . 19102926 .
8. van Doorn R, Dijkman R, Vermeer MH, Out-Luiting JJ, van der Raaij-Helmer EM, Willemze R, Tensen CP . Aberrant expression of the tyrosine kinase receptor EphA4 and the transcription factor twist in Sézary syndrome identified by gene expression analysis . Cancer Research . 64 . 16 . 5578–86 . Aug 2004 . 15313894 . 10.1158/0008-5472.CAN-04-1253 . 6506412 .
9. Web site: TWIST1-related craniosynostosis (Concept Id: C4551902) - MedGen - NCBI . 2023-07-17 . www.ncbi.nlm.nih.gov.
10. Khan MA, Chen HC, Zhang D, Fu J . Twist: a molecular target in cancer therapeutics . Tumour Biology . 34 . 5 . 2497–506 . Oct 2013 . 23873099 . 10.1007/s13277-013-1002-x . 498698 .
11. Puisieux A, Valsesia-Wittmann S, Ansieau S . A twist for survival and cancer progression . British Journal of Cancer . 94 . 1 . 13–7 . Jan 2006 . 16306876 . 2361066 . 10.1038/sj.bjc.6602876 .
12. Roberts CM, Tran MA, Pitruzzello MC, Wen W, Loeza J, Dellinger TH, Mor G, Glackin CA . TWIST1 drives cisplatin resistance and cell survival in an ovarian cancer model, via upregulation of GAS6, L1CAM, and Akt signalling . Scientific Reports . 6 . 37652 . 2016 . 27876874 . 5120297 . 10.1038/srep37652 . 2016NatSR...637652R .
13. Wu KJ, Yang MH . Epithelial-mesenchymal transition and cancer stemness: the Twist1-Bmi1 connection . Bioscience Reports . 31 . 6 . 449–55 . Dec 2011 . 21919891 . 10.1042/BSR20100114 . 16648243 .
14. Zhuo WL, Wang Y, Zhuo XL, Zhang YS, Chen ZT . Short interfering RNA directed against TWIST, a novel zinc finger transcription factor, increases A549 cell sensitivity to cisplatin via MAPK/mitochondrial pathway . Biochemical and Biophysical Research Communications . 369 . 4 . 1098–102 . May 2008 . 18331824 . 10.1016/j.bbrc.2008.02.143 .
15. Zhao XL, Sun T, Che N, Sun D, Zhao N, Dong XY, Gu Q, Yao Z, Sun BC . Promotion of hepatocellular carcinoma metastasis through matrix metalloproteinase activation by epithelial-mesenchymal transition regulator Twist1 . Journal of Cellular and Molecular Medicine . 15 . 3 . 691–700 . Mar 2011 . 20219012 . 3922390 . 10.1111/j.1582-4934.2010.01052.x .
16. Okamura H, Yoshida K, Haneji T . Negative regulation of TIMP1 is mediated by transcription factor TWIST1 . International Journal of Oncology . 35 . 1 . 181–6 . Jul 2009 . 19513566 . 10.3892/ijo_00000327 . free .
17. Hamamori Y, Sartorelli V, Ogryzko V, Puri PL, Wu HY, Wang JY, Nakatani Y, Kedes L . Regulation of histone acetyltransferases p300 and PCAF by the bHLH protein twist and adenoviral oncoprotein E1A . Cell . 96 . 3 . 405–13 . Feb 1999 . 10025406 . 10.1016/S0092-8674(00)80553-X . 15808193 . free .
18. El Ghouzzi V, Legeai-Mallet L, Aresta S, Benoist C, Munnich A, de Gunzburg J, Bonaventure J . Saethre-Chotzen mutations cause TWIST protein degradation or impaired nuclear location . Human Molecular Genetics . 9 . 5 . 813–9 . Mar 2000 . 10749989 . 10.1093/hmg/9.5.813 . free .