PMID- 24292681
OWN - NLM
STAT- MEDLINE
DCOM- 20150428
LR  - 20181202
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 33
IP  - 47
DP  - 2014 Nov 20
TI  - The role of p21(waf1/cip1) and p27(Kip1) in HDACi-mediated tumor cell death and 
      cell cycle arrest in the Emu-myc model of B-cell lymphoma.
PG  - 5415-23
LID - 10.1038/onc.2013.482 [doi]
AB  - Following the establishment of histone deacetylases (HDACs) as promising 
      therapeutic targets for the reversal of aberrant epigenetic states associated 
      with cancer, the development of HDAC inhibitors (HDACi) and their underlying 
      mechanisms of action has been a significant area of scientific interest. HDACi 
      induce diverse biological responses including the inhibition of cell 
      proliferation by blocking progression through the G1 or G2/M phases of the cell 
      cycle. As a putative tumor-suppressor protein, p21(waf1/cip1) influences cell 
      proliferation by inhibiting the activity of cyclin-cyclin-dependent kinase (CDK) 
      complexes at the G1/S and G2/M cell cycle checkpoints. HDACi transcriptionally 
      activate CDKN1A, and it has been proposed that induction of p21(waf1/cip1) can 
      determine if a cell undergoes apoptosis or cell cycle arrest following HDACi 
      treatment. In the Emu-myc transgenic mouse model of B-cell lymphoma, knockout of 
      cdkn1a had no effect on disease latency, indicating that p21(waf1/cip1) did not 
      function as a tumor suppressor in this system. Although HDACi robustly induced 
      expression of p21(waf1/cip1) in wild-type Emu-myc lymphomas, deletion of cdkn1a 
      did not sensitize the lymphoma cells to HDACi-induced apoptosis and HDACi-induced 
      cell cycle arrest still occurred. However, knockdown of cdkn1b in cdkn1a knockout 
      lymphomas resulted in defective vorinostat-mediated arrest at G1/S indicating an 
      essential role of p27(Kip1) in mediating this biological response to vorinostat. 
      These data demonstrate that induction of cdkn1a does not regulate HDACi-mediated 
      tumor cell apoptosis and refute the notion that p21(waf1/cip1) is an obligate 
      mediator of HDACi-induced cell cycle arrest.
FAU - Newbold, A
AU  - Newbold A
AD  - Cancer Therapeutics Program, Gene Regulation Laboratory, The Peter MacCallum 
      Cancer Institute, St Andrews Place, East Melbourne, Victoria, Australia.
FAU - Salmon, J M
AU  - Salmon JM
AD  - Cancer Therapeutics Program, Gene Regulation Laboratory, The Peter MacCallum 
      Cancer Institute, St Andrews Place, East Melbourne, Victoria, Australia.
FAU - Martin, B P
AU  - Martin BP
AD  - Cancer Therapeutics Program, Gene Regulation Laboratory, The Peter MacCallum 
      Cancer Institute, St Andrews Place, East Melbourne, Victoria, Australia.
FAU - Stanley, K
AU  - Stanley K
AD  - Cancer Therapeutics Program, Gene Regulation Laboratory, The Peter MacCallum 
      Cancer Institute, St Andrews Place, East Melbourne, Victoria, Australia.
FAU - Johnstone, R W
AU  - Johnstone RW
AD  - 1] Cancer Therapeutics Program, Gene Regulation Laboratory, The Peter MacCallum 
      Cancer Institute, St Andrews Place, East Melbourne, Victoria, Australia [2] The 
      Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, 
      Victoria, Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131202
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Cdkn1a protein, mouse)
RN  - 0 (Cdkn1b protein, mouse)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p21)
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 0 (Hydroxamic Acids)
RN  - 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27)
RN  - 58IFB293JI (Vorinostat)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects/genetics
MH  - Cell Cycle Checkpoints
MH  - Cell Death/drug effects/genetics
MH  - Cyclin-Dependent Kinase Inhibitor p21/*genetics/metabolism
MH  - Cyclin-Dependent Kinase Inhibitor p27/*genetics/metabolism
MH  - Disease Models, Animal
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Genes, Tumor Suppressor
MH  - Genes, myc
MH  - Histone Deacetylase Inhibitors/*pharmacology
MH  - Hydroxamic Acids/pharmacology
MH  - Lymphoma, B-Cell/drug therapy/*genetics/*pathology
MH  - Male
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Vorinostat
EDAT- 2013/12/03 06:00
MHDA- 2015/04/29 06:00
CRDT- 2013/12/03 06:00
PHST- 2013/04/16 00:00 [received]
PHST- 2013/10/02 00:00 [revised]
PHST- 2013/10/07 00:00 [accepted]
PHST- 2013/12/03 06:00 [entrez]
PHST- 2013/12/03 06:00 [pubmed]
PHST- 2015/04/29 06:00 [medline]
AID - onc2013482 [pii]
AID - 10.1038/onc.2013.482 [doi]
PST - ppublish
SO  - Oncogene. 2014 Nov 20;33(47):5415-23. doi: 10.1038/onc.2013.482. Epub 2013 Dec 2.