title: Twist1 and Snail link Hedgehog signaling to tumor-initiating cell-like properties and acquired chemoresistance independently of ABC transporters.
abstract: The Hedgehog (Hh) signaling pathway has been implicated in acquired chemoresistance. However, it remains unclear whether and how the Hh pathway may maintain the chemoresistant phenotype by controlling the tumor-initiating cell-like properties of acquired chemoresistant cancer cells. In this study, using well-established acquired chemoresistant cancer cells and chemosensitive KB cancer cells with artificially elevated Hh pathway activity, we found that Hh pathway activity may transcriptionally control the expression of twist1 and snail, thereby maintaining the tumor-initiating cell-like properties and consequently the chemoresistant phenotype. Meanwhile, we obtained direct evidence that twist1, which may amplify Hh signaling activity and plays an essential role in limb development, is a direct transcriptional target of Gli, similar to snail. We further observed that the expression of ATP-binding cassette (ABC) transporters was dispensable for the chemoresistance mediated by twist1 and snail. Collectively, these findings demonstrate that twist1, together with snail, links the Hh pathway to the tumor-initiating cell-like properties of chemoresistant cells. This consequently promotes chemoresistance independently of ABC transporters, thereby contributing to future development of strategies for combating chemoresistance through Hh pathway interference. Furthermore, our finding that twist1 is a direct target of the transcription factor Gli improves the interpretation of the association between twist1 and the Hh pathway and the nature of the signaling transduction of the Hh pathway.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Kong
authors.forename: Yuanqiu
authors.initials: Y
authors.lastname: Peng
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Hong
authors.initials: H
authors.lastname: Xin
authors.forename: Xia
authors.initials: X
authors.lastname: Zhan
authors.forename: Wenfu
authors.initials: W
authors.lastname: Tan
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D041681:NIH 3T3 Cells; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis*; D051879:Twist-Related Protein 1 / Q000096:biosynthesis*; D014750:Vincristine / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D053823:Hedgehog Proteins; D009687:Nuclear Proteins; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D014750:Vincristine
keywords: Acquired chemoresistance; Hedgehog; Snail; Tumor-initiating cell-like properties; Twist1