title: The role of p21(waf1/cip1) and p27(Kip1) in HDACi-mediated tumor cell death and cell cycle arrest in the Eμ-myc model of B-cell lymphoma.
abstract: 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 Eμ-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 Eμ-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.
authors.affiliation: Cancer Therapeutics Program, Gene Regulation Laboratory, The Peter MacCallum Cancer Institute, St Andrews Place, East Melbourne, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Newbold
authors.affiliation: Cancer Therapeutics Program, Gene Regulation Laboratory, The Peter MacCallum Cancer Institute, St Andrews Place, East Melbourne, Victoria, Australia.
authors.forename: J M
authors.initials: JM
authors.lastname: Salmon
authors.affiliation: Cancer Therapeutics Program, Gene Regulation Laboratory, The Peter MacCallum Cancer Institute, St Andrews Place, East Melbourne, Victoria, Australia.
authors.forename: B P
authors.initials: BP
authors.lastname: Martin
authors.affiliation: Cancer Therapeutics Program, Gene Regulation Laboratory, The Peter MacCallum Cancer Institute, St Andrews Place, East Melbourne, Victoria, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Stanley
authors.affiliation: 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.
authors.forename: R W
authors.initials: RW
authors.lastname: Johnstone
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D016259:Genes, myc; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D008297:Male; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000077337:Vorinostat
chemical_list: C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077337:Vorinostat