PMID- 26300003
OWN - NLM
STAT- MEDLINE
DCOM- 20170905
LR  - 20181113
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 35
IP  - 20
DP  - 2016 May 19
TI  - Dysregulated CRTC1 activity is a novel component of PGE2 signaling that 
      contributes to colon cancer growth.
PG  - 2602-14
LID - 10.1038/onc.2015.283 [doi]
AB  - First identified as a dedicated CREB (cAMP response element-binding protein) 
      co-activator, CRTC1 (CREB-regulated transcription co-activator 1) has been widely 
      implicated in various neuronal functions because of its predominant expression in 
      the brain. However, recent evidences converge to indicate that CRTC1 is 
      aberrantly activated in an expanding number of adult malignancies. In this study, 
      we provide strong evidences of enhanced CRTC1 protein content and transcriptional 
      activity in mouse models of sporadic (APC(min/+) mice) or colitis-associated 
      colon cancer azoxymethane/dextran sulfate sodium (AOM/DSS-treated mice), and in 
      human colorectal tumors specimens compared with adjacent normal mucosa. Among 
      signals that could trigger CRTC1 activation during colonic carcinogenesis, we 
      demonstrate that treatment with cyclooxygenase 2 (COX2) inhibitors reduced 
      nuclear CRTC1 active form levels in colonic tumors of APC(min/+) or AOM/DSS mice. 
      In accordance, prostaglandins E2 (PGE2) exposure to human colon cancer cell lines 
      promoted CRTC1 dephosphorylation and parallel nuclear translocation, resulting in 
      enhanced CRTC1 transcriptional activity, through EP1 and EP2 receptors signaling 
      and consecutive calcineurin and protein kinase A activation. In vitro CRTC1 loss 
      of function in colon cancer cell lines was associated with reduced viability and 
      cell division rate as well as enhanced chemotherapy-induced apoptosis on PGE2 
      treatment. Conversely, CRTC1 stable overexpression significantly increased 
      colonic xenografts tumor growth, therefore demonstrating the role of CRTC1 
      signaling in colon cancer progression. Identification of the transcriptional 
      program triggered by enhanced CRTC1 expression during colonic carcinogenesis, 
      revealed some notable pro-tumorigenic CRTC1 target genes including NR4A2, COX2, 
      amphiregulin (AREG) and IL-6. Finally, we demonstrate that COX2, AREG and IL-6 
      promoter activities triggered by CRTC1 are dependent on functional AP1 and CREB 
      transcriptional partners. Overall, our study establishes CRTC1 as new mediator of 
      PGE2 signaling, unravels the importance of its dysregulation in colon cancer and 
      strengthens its use as a bona fide cancer marker.
FAU - Schumacher, Y
AU  - Schumacher Y
AD  - Inserm U1016, Institut Cochin, Paris, France.
AD  - CNRS UMR 8104, Paris, France.
AD  - Universite Paris Descartes, Paris, France.
AD  - Universite Paris Diderot, Paris, France.
FAU - Aparicio, T
AU  - Aparicio T
AD  - Gastroenterology and Digestive Oncology Unit, Avicenne Hospital, HUPSSD, APHP, 
      Universite Paris 13, Bobigny, France.
FAU - Ourabah, S
AU  - Ourabah S
AD  - Inserm U1016, Institut Cochin, Paris, France.
AD  - CNRS UMR 8104, Paris, France.
AD  - Universite Paris Descartes, Paris, France.
FAU - Baraille, F
AU  - Baraille F
AD  - Inserm U1016, Institut Cochin, Paris, France.
AD  - CNRS UMR 8104, Paris, France.
AD  - Universite Paris Descartes, Paris, France.
FAU - Martin, A
AU  - Martin A
AD  - Pathology Unit, Avicenne Hospital, HUPSSD, APHP, Universite Paris 13, Bobigny, 
      France.
FAU - Wind, P
AU  - Wind P
AD  - Digestive Surgery Unit, Avicenne Hospital, HUPSSD, APHP, Universite Paris 13, 
      Bobigny, France.
FAU - Dentin, R
AU  - Dentin R
AD  - Inserm U1016, Institut Cochin, Paris, France.
AD  - CNRS UMR 8104, Paris, France.
AD  - Universite Paris Descartes, Paris, France.
FAU - Postic, C
AU  - Postic C
AD  - Inserm U1016, Institut Cochin, Paris, France.
AD  - CNRS UMR 8104, Paris, France.
AD  - Universite Paris Descartes, Paris, France.
FAU - Guilmeau, S
AU  - Guilmeau S
AD  - Inserm U1016, Institut Cochin, Paris, France.
AD  - CNRS UMR 8104, Paris, France.
AD  - Universite Paris Descartes, Paris, France.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150824
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (CRTC1 protein, human)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (Receptors, Prostaglandin E, EP1 Subtype)
RN  - 0 (Receptors, Prostaglandin E, EP2 Subtype)
RN  - 0 (Transcription Factor AP-1)
RN  - 0 (Transcription Factors)
RN  - K7Q1JQR04M (Dinoprostone)
SB  - IM
MH  - Carcinogenesis
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Colonic Neoplasms/*pathology
MH  - Cyclic AMP Response Element-Binding Protein/metabolism
MH  - Dinoprostone/*metabolism
MH  - Humans
MH  - Receptors, Prostaglandin E, EP1 Subtype/metabolism
MH  - Receptors, Prostaglandin E, EP2 Subtype/metabolism
MH  - *Signal Transduction
MH  - Transcription Factor AP-1/metabolism
MH  - Transcription Factors/*metabolism
EDAT- 2015/08/25 06:00
MHDA- 2017/09/07 06:00
CRDT- 2015/08/25 06:00
PHST- 2014/08/16 00:00 [received]
PHST- 2015/05/27 00:00 [revised]
PHST- 2015/06/05 00:00 [accepted]
PHST- 2015/08/25 06:00 [entrez]
PHST- 2015/08/25 06:00 [pubmed]
PHST- 2017/09/07 06:00 [medline]
AID - onc2015283 [pii]
AID - 10.1038/onc.2015.283 [doi]
PST - ppublish
SO  - Oncogene. 2016 May 19;35(20):2602-14. doi: 10.1038/onc.2015.283. Epub 2015 Aug 
      24.