PMID- 33323967
OWN - NLM
STAT- MEDLINE
DCOM- 20210728
LR  - 20210728
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 40
IP  - 6
DP  - 2021 Feb
TI  - Men1 disruption in Nkx3.1-deficient mice results in AR(low)/CD44(+) microinvasive 
      carcinoma development with the dysregulated AR pathway.
PG  - 1118-1127
LID - 10.1038/s41388-020-01589-1 [doi]
AB  - Dysregulated androgen receptor (AR) plays a crucial role in prostate cancer (PCa) 
      development, though further factors involved in its regulation remain to be 
      identified. Recently, paradoxical results were reported on the implication of the 
      MEN1 gene in PCa. To dissect its role in prostate luminal cells, we generated a 
      mouse model with inducible Men1 disruption in Nkx3.1-deficient mice in which 
      mouse prostatic intraepithelial neoplasia (mPIN) occur. Prostate glands from 
      mutant and control mice were analyzed pathologically and molecularly; cellular 
      and molecular analyses were carried out in PCa cell lines after MEN1 knockdown 
      (KD) by siRNA. Double-mutant mice developed accelerated mPIN and later displayed 
      microinvasive adenocarcinoma. Markedly, early-stage lesions exhibited a decreased 
      expression of AR and its target genes, accompanied by reduced CK18 and E-cadherin 
      expression, suggesting a shift from a luminal to a dedifferentiated epithelial 
      phenotype. Intriguingly, over 60% of menin-deficient cells expressed CD44 at a 
      later stage. Furthermore, MEN1 KD led to the increase in CD44 expression in PC3 
      cells re-expressing AR. Menin bound to the proximal AR promoter and regulated AR 
      transcription via the H3K4me3 histone mark. Interestingly, the cell proliferation 
      of AR-dependent cells (LNCaP, 22Rv1, and VCaP), but not of AR-independent cells 
      (DU145, PC3), responded strongly to MEN1 silencing. Finally, menin expression was 
      found reduced in some human PCa. These findings highlight the regulation of the 
      AR promoter by menin and the crosstalk between menin and the AR pathway. Our data 
      could be useful for better understanding the increasingly reported 
      AR-negative/NE-negative subtype of PCa and the mechanisms underlying its 
      development.
FAU - Teinturier, Romain
AU  - Teinturier R
AD  - Universite Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre 
      Leon Berard, Centre de recherche en cancerologie de Lyon, 69008, Lyon, France.
AD  - Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, 
      Sweden.
FAU - Luo, Yakun
AU  - Luo Y
AD  - Universite Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre 
      Leon Berard, Centre de recherche en cancerologie de Lyon, 69008, Lyon, France.
FAU - Decaussin-Petrucci, Myriam
AU  - Decaussin-Petrucci M
AD  - Universite Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre 
      Leon Berard, Centre de recherche en cancerologie de Lyon, 69008, Lyon, France.
AD  - Centre de Biologie et d'Anatomopathologie Sud, Centre Hospitalier Lyon Sud, 
      Hospices Civils de Lyon, Pierre Benite, 69495, Lyon, France.
FAU - Vlaeminck-Guillem, Virginie
AU  - Vlaeminck-Guillem V
AD  - Universite Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre 
      Leon Berard, Centre de recherche en cancerologie de Lyon, 69008, Lyon, France.
AD  - Centre de Biologie et d'Anatomopathologie Sud, Centre Hospitalier Lyon Sud, 
      Hospices Civils de Lyon, Pierre Benite, 69495, Lyon, France.
FAU - Vacherot, Francis
AU  - Vacherot F
AD  - Univ Paris Est Creteil, TRePCa, F-94010, Creteil, France.
FAU - Firlej, Virginie
AU  - Firlej V
AD  - Univ Paris Est Creteil, TRePCa, F-94010, Creteil, France.
AD  - Hopitaux Universitaires Henri Mondor, Plateforme de Ressources Biologiques, 
      F-94000, Creteil, France.
FAU - Bonnavion, Remy
AU  - Bonnavion R
AUID- ORCID: 0000-0002-7389-4282
AD  - Universite Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre 
      Leon Berard, Centre de recherche en cancerologie de Lyon, 69008, Lyon, France.
AD  - Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
FAU - Abou Ziki, Razan
AU  - Abou Ziki R
AD  - Universite Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre 
      Leon Berard, Centre de recherche en cancerologie de Lyon, 69008, Lyon, France.
FAU - Gherardi, Samuele
AU  - Gherardi S
AD  - Universite Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre 
      Leon Berard, Centre de recherche en cancerologie de Lyon, 69008, Lyon, France.
FAU - Goddard, Isabelle
AU  - Goddard I
AD  - Laboratoire des Modeles Tumoraux, Fondation Synergie Lyon Cancer, Universite de 
      Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Leon 
      Berard, Centre de recherche en cancerologie de Lyon (CRCL), 69373, Lyon, France.
FAU - Gadot, Nicolas
AU  - Gadot N
AD  - Plateforme Anatomopathologie Recherche, Universite de Lyon, Universite Claude 
      Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Leon Berard, Centre de recherche 
      en cancerologie de Lyon (CRCL), 69373, Lyon, France.
FAU - Bertolino, Philippe
AU  - Bertolino P
AD  - Universite Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre 
      Leon Berard, Centre de recherche en cancerologie de Lyon, 69008, Lyon, France.
FAU - Le Romancer, Muriel
AU  - Le Romancer M
AD  - Universite Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre 
      Leon Berard, Centre de recherche en cancerologie de Lyon, 69008, Lyon, France.
FAU - Zhang, Chang Xian
AU  - Zhang CX
AUID- ORCID: 0000-0002-5443-8951
AD  - Universite Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre 
      Leon Berard, Centre de recherche en cancerologie de Lyon, 69008, Lyon, France. 
      chang.zhang@lyon.unicancer.fr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201215
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (AR protein, mouse)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (Hyaluronan Receptors)
RN  - 0 (Men1 protein, mouse)
RN  - 0 (Nkx3-1 protein, mouse)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Receptors, Androgen)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Animals
MH  - Cell Proliferation/genetics
MH  - Disease Models, Animal
MH  - Gene Expression Regulation, Neoplastic/genetics
MH  - Homeodomain Proteins/*genetics
MH  - Humans
MH  - Hyaluronan Receptors/*genetics
MH  - Male
MH  - Mice
MH  - Neoplasm Invasiveness/genetics/pathology
MH  - Prostate/metabolism/pathology
MH  - Prostatic Intraepithelial Neoplasia/*genetics/pathology
MH  - Proto-Oncogene Proteins/*genetics
MH  - Receptors, Androgen/*genetics
MH  - Signal Transduction
MH  - Transcription Factors/*genetics
EDAT- 2020/12/17 06:00
MHDA- 2021/07/29 06:00
CRDT- 2020/12/16 05:33
PHST- 2020/06/05 00:00 [received]
PHST- 2020/11/26 00:00 [accepted]
PHST- 2020/11/17 00:00 [revised]
PHST- 2020/12/17 06:00 [pubmed]
PHST- 2021/07/29 06:00 [medline]
PHST- 2020/12/16 05:33 [entrez]
AID - 10.1038/s41388-020-01589-1 [pii]
AID - 10.1038/s41388-020-01589-1 [doi]
PST - ppublish
SO  - Oncogene. 2021 Feb;40(6):1118-1127. doi: 10.1038/s41388-020-01589-1. Epub 2020 
      Dec 15.