The Peter MacCallum Cancer Institute

East Melbourne, Australia

The Peter MacCallum Cancer Institute

East Melbourne, Australia

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Newbold A.,The Peter MacCallum Cancer Institute | Salmon J.M.,The Peter MacCallum Cancer Institute | Martin B.P.,The Peter MacCallum Cancer Institute | Stanley K.,The Peter MacCallum Cancer Institute | And 2 more authors.
Oncogene | Year: 2013

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, p21waf1/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 p21waf1/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 p21waf1/cip1 did not function as a tumor suppressor in this system. Although HDACi robustly induced expression of p21waf1/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 p27Kip1 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 p21waf1/cip1 is an obligate mediator of HDACi-induced cell cycle arrest.Oncogene advance online publication, 2 December 2013; doi:10.1038/onc.2013.482.


Newbold A.,The Peter MacCallum Cancer Institute | Salmon J.M.,The Peter MacCallum Cancer Institute | Martin B.P.,The Peter MacCallum Cancer Institute | Stanley K.,The Peter MacCallum Cancer Institute | Johnstone R.W.,Victoria University of Melbourne
Oncogene | Year: 2014

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.


PubMed | The Peter MacCallum Cancer Institute and Victoria University of Melbourne
Type: Journal Article | Journal: Oncogene | Year: 2014

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 E-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 E-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.


PubMed | The Peter MacCallum Cancer Institute
Type: Journal Article | Journal: Cancer research | Year: 2011

The concept of personalized anticancer therapy is based on the use of targeted therapeutics through in-depth knowledge of the molecular mechanisms of action of these agents when used alone and in combination. We have identified the apoptotic proteins and pathways necessary for synergistic tumor cell apoptosis and in vivo antitumor responses seen when the HDAC inhibitor vorinostat is combined with the BH3-mimetic ABT-737 in lymphomas overexpressing Bcl-2. Vorinostat primes tumors overexpressing Bcl-2 for rapid ABT-737-mediated apoptosis by inducing expression of the BH3-only gene bmf. Moreover, these synergistic effects of vorinostat/ABT-737 were blunted in cells with an inactive p53 pathway or in cells lacking expression of the p53 target gene, noxa. These studies show the important and complex functional interaction between specific proapoptotic BH3-only proteins and the BH3-mimetic compound ABT-737 and provide the most comprehensive functional link between tumor genotype and the apoptotic and therapeutic effects of HDACi combined with ABT-737.

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