17 research outputs found
Fascin-1 expression is associated with neuroendocrine prostate cancer and directly suppressed by androgen receptor
Endocrine cancerCàncer endocríCáncer endocrinoBackground
Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer, arising from resistance to androgen-deprivation therapies. However, the molecular mechanisms associated with NEPC development and invasiveness are still poorly understood. Here we investigated the expression and functional significance of Fascin-1 (FSCN1), a pro-metastasis actin-bundling protein associated with poor prognosis of several cancers, in neuroendocrine differentiation of prostate cancer.
Methods
Differential expression analyses using Genome Expression Omnibus (GEO) database, clinical samples and cell lines were performed. Androgen or antagonist’s cellular treatments and knockdown experiments were used to detect changes in cell morphology, molecular markers, migration properties and in vivo tumour growth. Chromatin immunoprecipitation-sequencing (ChIP-Seq) data and ChIP assays were analysed to decipher androgen receptor (AR) binding.
Results
We demonstrated that FSCN1 is upregulated during neuroendocrine differentiation of prostate cancer in vitro, leading to phenotypic changes and NEPC marker expression. In human prostate cancer samples, FSCN1 expression is restricted to NEPC tumours. We showed that the androgen-activated AR downregulates FSCN1 expression and works as a transcriptional repressor to directly suppress FSCN1 expression. AR antagonists alleviate this repression. In addition, FSCN1 silencing further impairs in vivo tumour growth.
Conclusion
Collectively, our findings identify FSCN1 as an AR-repressed gene. Particularly, it is involved in NEPC aggressiveness. Our results provide the rationale for the future clinical development of FSCN1 inhibitors in NEPC patients.This work was funded by CNRS (Centre national de recherche scientifique), INSERM (Institut national de la santé et de la recherche médicale), Université de Lille, Institut Pasteur de Lille, and supported by grants from Ligue nationale contre le Cancer (Comité de l’Aisne), Institut national du cancer (INCa_4419), ARTP (Association de Recherche sur les tumeurs de prostate). This work is supported by a grant from Contrat de Plan Etat-Région CPER Cancer 2015–2020. Work performed at the laboratory of TVT was supported by Spanish Plan Estatal de I + D + I (PID2019-108008RJ-I00), AECC (INVES20036TIAN), Ramón y Cajal investigator programme (RYC2020-029098-I), and FERO Foundation. CD was supported by Institut Pasteur de Lille, Conseil Régional des Hauts-de-France and Fondation pour la Recherche Médicale (FRM)
Single-molecule conductance of a chemically modified, {\pi}-extended tetrathiafulvalene and its charge-transfer complex with F4TCNQ
We describe the synthesis and single molecule electrical transport properties
of a molecular wire containing a -extended tetrathiafulvalene (exTTF)
group and its charge-transfer complex with F4TCNQ. We form single molecule
junctions using the in-situ break junction technique using a home-built
scanning tunneling microscope with a range of conductance between 10 G
down to 10 G. Within this range we do not observe a clear
conductance signature of the neutral parent molecule, suggesting either that
its conductance is too low or that it does not form stable junctions.
Conversely, we do find a clear conductance signature in the experiments carried
out on the charge-transfer complex. Due to the fact we expected this species to
have a higher conductance than the neutral molecule, we believe this supports
the idea that the conductance of the neutral molecule is very low, below our
measurement sensitivity. This is further supported by our theoretical
calculations. To the best of our knowledge, these are the first reported single
molecule conductance measurements on a molecular charge-transfer species
New insights in the epigenetic control of EMT
The
epithelial
to
mesenchymal
transition
(EMT)
is
a
highly
conserved
cellular
program
that
allows
well-‐differentiated
epithelial
cells
to
convert
to
motile
mesenchymal
cells.
EMT
is
critical
for
appropriate
embryogenesis
and
plays
a
crucial
role
in
tumorigenesis
and
cancer
progression.
At
this
regard,
it
has
become
increasingly
evident
that,
in
addition
to
genetic
alterations,
tumour
development
involves
the
alteration
of
gene
expression
patterns
owing
to
epigenetic
changes.
Taking
this
into
account,
this
thesis
mainly
addresses
the
description
of
new
molecular
epigenetic
mechanisms
underlying
one
of
the
hallmark
processes
governing
EMT,
the
Snail1-‐mediated
E-‐cadherin
repression.
Indeed,
our
results
demonstrate
that
both
Polycomb
group
(PcG)
proteins
and
the
LOXL2
protein
are
involved
in
this
process.
Apart
from
providing
novel
insights
into
the
significance
of
these
proteins
in
tumor
progression,
our
work
uncovers
the
characterization
of
a
new
epigenetic
modification
carried
out
by
LOXL2;
H3K4
deamination.La
transició
epiteli-‐mesènquima
(EMT)
és
un
programa
cel·lular
molt
conservat
que
permet
a
les
cèl·lules
epitelials
convertir-‐se
en
cèl·lules
mesenquimals
indiferenciades.
La
EMT
és
un
procés
crucial
pel
desenvolupament
embrionari
i
per
la
progressió
tumoral.
A
aquest
respecte,
ha
esdevingut
cada
cop
més
evident
que
el
desenvolupament
tumoral
no
només
està
associat
a
alteracions
genètiques,
sinó
també
a
l'alteració
de
l’expressió
gènica
causada
per
canvis
epigenètics.
Tenint
això
en
compte,
aquesta
tesi
es
centra
en
la
descripció
de
nous
mecanismes
moleculars
en
l’àmbit
de
l’epigenètica
associats
a
un
dels
processos
clau
en
la
EMT,
la
repressió
de
la
E-‐
cadherina
mitjançada
pel
factor
de
transcripció
Snail1.
De
fet,
els
nostres
resultats
demostren
que
tant
les
proteïnes
del
grup
Polycomb
(PcG)
com
la
proteïna
LOXL2
estan
implicades
en
aquest
procés.
A
part
de
proporcionar
nova
informació
respecte
la
importància
d'aquestes
proteïnes
en
la
progressió
tumoral,
la
nostra
feina
ha
permès
la
caracterització
d'una
nova
modificació
epigenètica
duta
a
terme
per
la
proteïna
LOXL2;
la
deaminació
de
H3K4
Regulation of heterochromatin transcription by Snail1/LOXL2 during epithelial-to-mesenchymal transition
Although heterochromatin is enriched with repressive traits, it is also actively transcribed, giving rise to large amounts of noncoding RNAs. Although these RNAs are responsible for the formation and maintenance of heterochromatin, little is known about how their transcription is regulated. Here, we show that the Snail1 transcription factor represses mouse pericentromeric transcription, acting through the H3K4 deaminase LOXL2. Since Snail1 plays a key role in the epithelial-to-mesenchymal transition (EMT), we analyzed the regulation of heterochromatin transcription in this process. At the onset of EMT, one of the major structural heterochromatin proteins, HP1α, is transiently released from heterochromatin foci in a Snail1/LOXL2-dependent manner, concomitantly with a downregulation of major satellite transcription. Moreover, preventing the downregulation of major satellite transcripts compromised the migratory and invasive behavior of mesenchymal cells. We propose that Snail1 regulates heterochromatin transcription through LOXL2, thus creating the favorable transcriptional state necessary for completing EMT
Lysyl oxidase-like 2 deaminates lysine 4 in histone H3
Methylation of lysine 4 (K4) within histone H3 has been linked to active transcription and is removed by LSD1 and the JmjC domain-containing proteins by amino-oxidation or hydroxylation, respectively. Here, we describe the deamination catalyzed by Lysyl oxidase-like 2 protein (LOXL2) as an unconventional chemical mechanism for H3K4 modification. Infrared spectroscopy and mass spectrometry analyses demonstrated that recombinant LOXL2 specifically deaminates trimethylated H3K4. Moreover, LOXL2 activity is linked with the transcriptional control of CDH1 gene by regulating H3K4me3 deamination. These results reveal another H3 modification and provide a different mechanism for H3K4 modification
Advanced Prostate Cancer with ATM Loss: PARP and ATR Inhibitors
Inhibició de l’ATR; Resposta de danys a l’ADN; Càncer de pròstataInhibición de ATR; Respuesta al daño del ADN; Cancer de prostataATR inhibition; DNA damage response; Prostate cancerBackground
Deleterious ATM alterations are found in metastatic prostate cancer (PC); PARP inhibition has antitumour activity against this subset, but only some ATM loss PCs respond.
Objective
To characterise ATM-deficient lethal PC and to study synthetic lethal therapeutic strategies for this subset.
Design, setting, and participants
We studied advanced PC biopsies using validated immunohistochemical (IHC) and next-generation sequencing (NGS) assays. In vitro cell line models modified using CRISPR-Cas9 to impair ATM function were generated and used in drug-sensitivity and functional assays, with validation in a patient-derived model.
Outcome measurements and statistical analysis
ATM expression by IHC was correlated with clinical outcome using Kaplan-Meier curves and log-rank test; sensitivity to different drug combinations was assessed in the preclinical models.
Results and limitations
Overall, we detected ATM IHC loss in 68/631 (11%) PC patients in at least one biopsy, with synchronous and metachronous intrapatient heterogeneity; 46/71 (65%) biopsies with ATM loss had ATM mutations or deletions by NGS. ATM IHC loss was not associated with worse outcome from advanced disease, but ATM loss was associated with increased genomic instability (NtAI:number of subchromosomal regions with allelic imbalance extending to the telomere, p = 0.005; large-scale transitions, p = 0.05). In vitro, ATM loss PC models were sensitive to ATR inhibition, but had variable sensitivity to PARP inhibition; superior antitumour activity was seen with combined PARP and ATR inhibition in these models.
Conclusions
ATM loss in PC is not always detected by targeted NGS, associates with genomic instability, and is most sensitive to combined ATR and PARP inhibition.We gratefully acknowledge research funding for this work from Cancer Research UK, Prostate Cancer UK, the Movember Foundation through the London Movember Centre of Excellence ( CEO13_2-002 ), the Prostate Cancer Foundation (including Young Investigator Awards to Joaquin Mateo, Pasquale Rescigno, and Adam Sharp), Stand Up To Cancer, and the UK Department of Health through an Experimental Cancer Medicine Centre grant. Professor Johann de Bono is a National Institute for Health Research (NIHR) Senior Investigator; research at the Royal Marsden Hospital is supported by a Biomedical Research Centre grant. Part of this work was also funded by a Deparment of Defense CDMRP Impact Award (W81XWH-18-1-0756) to Joaquin Mateo and by Instituto de Salud Carlos III through Grant FI19/00280 to Sara Arce-Gallego, Grant CP19/00170 to Nicolás Herranz, and Grant PI18/01384 to Joaquin Mateo. The authors affiliated to VHIO acknowledge the “la Caixa” Foundation ( ID 100010434 ) for funding under agreement LCF/PR/PR17/51120011 and funding from Fundacion FERO and Moventia . This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 837900 . The funding organisations had no role in the design, conduction or data analysis of this project, neither in the manuscript preparation