Transcriptional network involving ERG and AR orchestrates Distal-less homeobox-1 mediated prostate cancer progression.

Androgen Antagonists / pharmacology Animals Azepines / pharmacology Cell Line, Tumor Disease Progression Gene Expression Regulation, Neoplastic Hepatocyte Nuclear Factor 3-alpha / genetics Homeodomain Proteins / genetics Humans Male Mice Mice, Knockout Mice, SCID Neoplasm Metastasis Oncogene Proteins, Fusion / genetics Promoter Regions, Genetic Prostate / drug effects Prostatic Neoplasms / drug therapy Protein Binding Receptors, Androgen / genetics Serine Endopeptidases / genetics Signal Transduction Survival Analysis Transcription Factors / genetics Transcription, Genetic Transcriptional Regulator ERG / genetics Triazoles / pharmacology Xenograft Model Antitumor Assays

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
07 09 2021
Historique:
received: 06 10 2020
accepted: 20 08 2021
entrez: 8 9 2021
pubmed: 9 9 2021
medline: 7 10 2021
Statut: epublish

Résumé

Distal-less homeobox-1 (DLX1) is a well-established non-invasive biomarker for prostate cancer (PCa) diagnosis, however, its mechanistic underpinnings in disease pathobiology are not known. Here, we reveal the oncogenic role of DLX1 and show that abrogating its function leads to reduced tumorigenesis and metastases. We observed that ~60% of advanced-stage and metastatic patients display higher DLX1 levels. Moreover, ~96% of TMPRSS2-ERG fusion-positive and ~70% of androgen receptor (AR)-positive patients show elevated DLX1, associated with aggressive disease and poor survival. Mechanistically, ERG coordinates with enhancer-bound AR and FOXA1 to drive transcriptional upregulation of DLX1 in ERG-positive background. However, in ERG-negative context, AR/AR-V7 and FOXA1 suffice to upregulate DLX1. Notably, inhibiting ERG/AR-mediated DLX1 transcription using BET inhibitor (BETi) or/and anti-androgen drugs reduce its expression and downstream oncogenic effects. Conclusively, this study establishes DLX1 as a direct-target of ERG/AR with an oncogenic role and demonstrates the clinical significance of BETi and anti-androgens for DLX1-positive patients.

Identifiants

DOI: 10.1038/s41467-021-25623-2 PMID: 34493733 PMC: PMC8423767
pubmed: 34493733
doi: 10.1038/s41467-021-25623-2
pii: 10.1038/s41467-021-25623-2
pmc: PMC8423767
doi:

Substances chimiques

(+)-JQ1 compound 0
Androgen Antagonists 0
Azepines 0
Distal-less homeobox proteins 0
ERG protein, human 0
FOXA1 protein, human 0
Hepatocyte Nuclear Factor 3-alpha 0
Homeodomain Proteins 0
Oncogene Proteins, Fusion 0
Receptors, Androgen 0
Transcription Factors 0
Transcriptional Regulator ERG 0
Triazoles 0
Serine Endopeptidases EC 3.4.21.-
TMPRSS2 protein, human EC 3.4.21.-

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

5325

Subventions

Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : DBT-Wellcome Trust India Alliance
ID : IA/S/19/2/504659
Pays : India
Organisme : NCI NIH HHS
ID : P01 CA163227
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA097186
Pays : United States

Informations de copyright

© 2021. The Author(s).

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Auteurs

Sakshi Goel (S)

Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, U.P., India.
ORCID: 0000-0002-5283-9049

Vipul Bhatia (V)

Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, U.P., India.
ORCID: 0000-0002-4091-8866

Sushmita Kundu (S)

Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, U.P., India.

Tanay Biswas (T)

Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, U.P., India.

Shannon Carskadon (S)

Vattikuti Urology Institute, Department of Urology, Henry Ford Health System, Detroit, MI, USA.

Nilesh Gupta (N)

Department of Pathology, Henry Ford Health System, Detroit, MI, USA.

Mohammad Asim (M)

Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.

Colm Morrissey (C)

Department of Urology, University of Washington, Seattle, WA, USA.

Nallasivam Palanisamy (N)

Vattikuti Urology Institute, Department of Urology, Henry Ford Health System, Detroit, MI, USA.

Bushra Ateeq (B)

Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, U.P., India. bushra@iitk.ac.in.
The Mehta Family Center for Engineering in Medicine, Indian Institute of Technology Kanpur, Kanpur, U.P., India. bushra@iitk.ac.in.
ORCID: 0000-0003-4682-9773

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Classifications MeSH

questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Hormones, substituts d'hormones et antagonistes d'hormones › Antihormones › Antagonistes des androgènes › Transcriptional network involving ERG and AR...
questionsmedicales.fr › Eucaryotes › Animaux › Transcriptional network involving ERG and AR...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azépines › Transcriptional network involving ERG and AR...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Transcriptional network involving ERG and AR...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Évolution de la maladie › Transcriptional network involving ERG and AR...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › Transcriptional network involving ERG and AR...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif hélice ailée › Facteurs de transcription Forkhead › Facteur nucléaire hépatocytaire HNF-3 alpha › Transcriptional network involving ERG and AR...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de liaison à l'ADN › Protéines à homéodomaine › Transcriptional network involving ERG and AR...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Transcriptional network involving ERG and AR...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Transcriptional network involving ERG and AR...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › Transcriptional network involving ERG and AR...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souches mutantes de souris › Souris SCID › Transcriptional network involving ERG and AR...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Métastase tumorale › Transcriptional network involving ERG and AR...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines de fusion oncogènes › Transcriptional network involving ERG and AR...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Éléments de régulation transcriptionnelle › Régions promotrices (génétique) › Transcriptional network involving ERG and AR...
questionsmedicales.fr › Tissus › Glandes exocrines › Prostate › Transcriptional network involving ERG and AR...
questionsmedicales.fr › Maladies urogénitales › Tumeurs de l'appareil urogénital › Tumeurs de l'appareil génital mâle › Tumeurs de la prostate › Transcriptional network involving ERG and AR...
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questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Régulateur transcriptionnel ERG › Transcriptional network involving ERG and AR...
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