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Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Histone deacetylase 2 modulates p53 transcriptional activities through regulation of p53-DNA binding activity
Kelly Lynn Harms1, Xinbin Chen
1Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Abstract:
Histone deacetylase (HDAC) inhibitors are emerging as promising cancer therapeutics. HDAC inhibitors have been found to induce cellular activities that are strikingly similar to p53-mediated responses to genotoxic stress. For example, HDAC inhibitors induce cell cycle arrest, apoptosis, and cellular senescence. Because at least 11 HDACs are affected by the current HDAC inhibitors, the HDAC critical for tumor cell survival and proliferation remains unknown. Thus, we sought to characterize the distinct roles of HDACs in the p53 pathway. Through the use of stable MCF7 cell lines which inducibly express short hairpin RNA targeting HDAC2, we found that HDAC2 plays important roles in the p53 pathway. Specifically, we found that knockdown of HDAC2 inhibited cellular proliferation in a dose-dependent manner which was also partly p53-dependent. Furthermore, knockdown of HDAC2 induced cellular senescence. Importantly, we found that knockdown of HDAC2 enhanced p53-dependent trans-repression and trans-activation of a subset of target genes. We found that the enhancement was due to increased p53-DNA binding activity but not alterations in p53 stability or posttranslational modification(s). Thus, for the first time, our data suggest that HDAC inhibitors function through the p53 pathway, at least in part, by activating p53-DNA binding activity.
Insights
Histone deacetylase (HDAC) inhibitors show promise in cancer therapy. This study reveals that HDAC2 knockdown inhibits cancer cell proliferation and induces senescence, partly via the p53 pathway by increasing p53-DNA binding.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Histone deacetylase (HDAC) inhibitors are emerging cancer therapeutics.
- HDAC inhibitors mimic p53-mediated responses to genotoxic stress, inducing cell cycle arrest, apoptosis, and senescence.
- The specific HDACs critical for tumor cell survival are largely unknown.
Purpose of the Study:
- To characterize the distinct roles of HDACs in the p53 pathway.
- To investigate the role of HDAC2 in cancer cell proliferation and senescence.
- To elucidate the mechanism by which HDAC inhibitors affect the p53 pathway.
Main Methods:
- Utilized stable MCF7 cell lines with inducible short hairpin RNA targeting HDAC2.
- Assessed the effects of HDAC2 knockdown on cellular proliferation, senescence, and p53 activity.
- Analyzed p53-DNA binding activity, stability, and posttranslational modifications.
Main Results:
- HDAC2 knockdown inhibited cellular proliferation in a dose-dependent and partly p53-dependent manner.
- Knockdown of HDAC2 induced cellular senescence.
- HDAC2 knockdown enhanced p53-dependent gene trans-repression and trans-activation by increasing p53-DNA binding activity, without altering p53 stability or modifications.
Conclusions:
- HDAC2 plays a significant role in the p53 pathway.
- HDAC inhibitors may function, in part, by activating p53-DNA binding activity.
- These findings provide novel insights into the mechanism of HDAC inhibitors in cancer therapy.
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