ArticleOncogene2018
Non-canonical activation of hedgehog in prostate cancer cells mediated by the interaction of transcriptionally active androgen receptor proteins with Gli3.
Article in Oncogene, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 38 citations in OpenAlex.
- From fungus fighter to cancer slayer: itraconazole as a multifaceted candidate for drug-resistant prostate cancer.Prostate cancer and prostatic diseases · 2026Review
- Multifaceted role of primary cilia and ciliary proteins: A potential nexus for hedgehog signaling and prostate cancer.Biochimica et biophysica acta. Molecular basis of disease · 2026Review
- GLI3 in cancer: a context-dependent regulator with diagnostic, prognostic, and therapeutic potential.Frontiers in immunology · 2026Review
- Germline-Somatic Liaison Dictates Cancer Subtypes via de novo Steroid Biosynthesis.Cancer discovery · 2025Article
- Oncogenic potential of truncated-Gli3 via the Gsk3β/Gli3/AR-V7 axis in castration-resistant prostate cancer.Oncogene · 2025Article
- Therapeutic Potential of Decoys for Prostate Cancers: A Review of Recent Updates.Current medicinal chemistry · 2024Review
- Positive correlation between the nuclear expression of GPER and pGLI3 in prostate cancer tissues from patients with different Gleason scores.Frontiers in endocrinology · 2024Article
- Prostate cancer patient stratification by molecular signatures in the Veterans Precision Oncology Data Commons.Cold Spring Harbor molecular case studies · 2023Article
- Malignant DFFB isoform switching promotes leukemia survival in relapse pediatric T-cell acute lymphoblastic leukemia.EJHaem · 2023Article
- Genetic alterations in MED12 promote castration-resistant prostate cancer through modulation of GLI3 signaling.Molecular biology research communications · 2023Article
- Fatty Acid Signaling Impacts Prostate Cancer Lineage Plasticity in an Autocrine and Paracrine Manner.Cancers · 2022Article
- Signaling Pathways and Targeted Therapies for Stem Cells in Prostate Cancer.ACS pharmacology & translational science · 2022Review
- Gender-related differentially expressed genes in pancreatic cancer: possible culprits or accomplices?Frontiers in genetics · 2022Article
- GLI3 Is Stabilized by SPOP Mutations and Promotes Castration Resistance via Functional Cooperation with Androgen Receptor in Prostate Cancer.Molecular cancer research : MCR · 2022Article
- Hedgehog/GLI1 Transcriptionally Regulates FANCD2 in Ovarian Tumor Cells: Its Inhibition Induces HR-Deficiency and Synergistic Lethality with PARP Inhibition.Neoplasia (New York, N.Y.) · 2021Article
- SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells.Scientific reports · 2021Article
- Hedgehog signaling in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment.Acta pharmaceutica Sinica. B · 2021Review
- The hedgehog pathway regulates cancer stem cells in serous adenocarcinoma of the ovary.Cellular oncology (Dordrecht, Netherlands) · 2020Article
- GLI3: a mediator of genetic diseases, development and cancer.Cell communication and signaling : CCS · 2020Review
- Comparison of the clinicopathological features of pancreatic solid pseudopapillary neoplasms between males and females: gender does matter.Histology and histopathology · 2020Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hedgehog (Hh) is an oncogenic signaling pathway that regulates the activity of Gli transcription factors. Canonical Hh is a Smoothened- (Smo-) driven process that alters the post-translational processing of Gli2/Gli3 proteins. Though evidence supports a role for Gli action in prostate cancer (PCa) cell growth and progression, there is little indication that Smo is involved. Here we describe a non-canonical means for activation of Gli transcription in PCa cells mediated by the binding of transcriptionally-active androgen receptors (ARs) to Gli3. Androgens stimulated reporter expression from a Gli-dependent promoter in a variety of AR + PCa cells and this activity was suppressed by an anti-androgen, Enz, or by AR knockdown. Androgens also upregulated expression of endogenous Gli-dependent genes. This activity was associated with increased intranuclear binding of Gli3 to AR that was antagonized by Enz. Fine mapping of the AR binding domain on Gli2 showed that AR recognizes the Gli protein processing domain (PPD) in the C-terminus. Mutations in the arginine-/serine repeat elements of the Gli2 PPD involved in phosphorylation and ubiquitinylation blocked the binding to AR. β-TrCP, a ubiquitin ligase that recognizes the Gli PPD, competed with AR for binding to this site. AR binding to Gli3 suppressed its proteolytic processing to the Gli3 repressor form (Gli3R) whereas AR knockdown increased Gli3R. Both full-length and truncated ARs were able to activate Gli transcription. Finally, we found that an ARbinding decoy polypeptide derived from the Gli2 C-terminus can compete with Gli3 for binding to AR. Exogenous overexpression of this decoy suppressed Gli transcriptional activity in PCa cells. Collectively, this work identifies a novel pathway for non-canonical activation of Hh signaling in PCa cells and identifies a means for interference that may have clinical relevance for PCa patients.
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