{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T16:46:33Z","timestamp":1790527593480,"version":"4.1.0"},"reference-count":278,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,17]],"date-time":"2020-09-17T00:00:00Z","timestamp":1600300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["1R01CA228137-01A1"],"award-info":[{"award-number":["1R01CA228137-01A1"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["W81XWH-17-1-0044"],"award-info":[{"award-number":["W81XWH-17-1-0044"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["W81XWH-19-1-0072"],"award-info":[{"award-number":["W81XWH-19-1-0072"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["W81XWH-19-1-0753"],"award-info":[{"award-number":["W81XWH-19-1-0753"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["W81XWH-20-1-0044"],"award-info":[{"award-number":["W81XWH-20-1-0044"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The hedgehog (HH) signaling pathway regulates normal cell growth and differentiation. As a consequence of improper control, aberrant HH signaling results in tumorigenesis and supports aggressive phenotypes of human cancers, such as neoplastic transformation, tumor progression, metastasis, and drug resistance. Canonical activation of HH signaling occurs through binding of HH ligands to the transmembrane receptor Patched 1 (PTCH1), which derepresses the transmembrane G protein-coupled receptor Smoothened (SMO). Consequently, the glioma-associated oncogene homolog 1 (GLI1) zinc-finger transcription factors, the terminal effectors of the HH pathway, are released from suppressor of fused (SUFU)-mediated cytoplasmic sequestration, permitting nuclear translocation and activation of target genes. Aberrant activation of this pathway has been implicated in several cancer types, including medulloblastoma, rhabdomyosarcoma, basal cell carcinoma, glioblastoma, and cancers of lung, colon, stomach, pancreas, ovarian, and breast. Therefore, several components of the HH pathway are under investigation for targeted cancer therapy, particularly GLI1 and SMO. GLI1 transcripts are reported to undergo alternative splicing to produce truncated variants: loss-of-function GLI1\u0394N and gain-of-function truncated GLI1 (tGLI1). This review covers the biochemical steps necessary for propagation of the HH activating signal and the involvement of aberrant HH signaling in human cancers, with a highlight on the tumor-specific gain-of-function tGLI1 isoform.<\/jats:p>","DOI":"10.3390\/cells9092114","type":"journal-article","created":{"date-parts":[[2020,9,17]],"date-time":"2020-09-17T08:29:43Z","timestamp":1600331383000},"page":"2114","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":167,"title":["Hedgehog Signaling and Truncated GLI1 in Cancer"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1455-3090","authenticated-orcid":false,"given":"Daniel","family":"Doheny","sequence":"first","affiliation":[{"name":"Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1962-5505","authenticated-orcid":false,"given":"Sara G.","family":"Manore","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5986-4952","authenticated-orcid":false,"given":"Grace L.","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Wen","family":"Lo","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA"},{"name":"Wake Forest Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1038\/287795a0","article-title":"Mutations affecting segment number and polarity in Drosophila","volume":"287","author":"Wieschaus","year":"1980","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2454","DOI":"10.1101\/gad.1693608","article-title":"Hedgehog: Functions and mechanisms","volume":"22","author":"Varjosalo","year":"2008","journal-title":"Genes Dev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.1101\/gad.938601","article-title":"Hedgehog signaling in animal development: Paradigms and principles","volume":"15","author":"Ingham","year":"2001","journal-title":"Genes Dev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1038\/nrd2086","article-title":"Targeting the Hedgehog pathway in cancer","volume":"5","author":"Rubin","year":"2006","journal-title":"Nat. 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