Investigation of the Pharmacological Inhibition of HDAC6 with Ricolinostat

Fengyu Zhang, Aaron Maguire, Ahlam Abdunnabi Ali, Irina Tikhonova, Niamh E Buckley, Fiona Furlong

Research output: Contribution to conferencePosterpeer-review

Abstract

The histone deacetylase 6 (HDAC6) protein is a unique member of the HDAC superfamily of deacetylating enzymes. At 1225 amino acids, it is a large multidomain protein uniquely consisting of 2 catalytic domains. Unlike other HDAC proteins, HDAC6 deacetylates several cytoplasmic proteins and HDAC6 functions are widely reported to contribute to tumorigenesis. Moderate to strong HDAC6 IHC expression has been associated with favourable outcomes in breast cancer that may be associated with the improved survival of estrogen positive breast cancers. Here we explore the anticancer activity of HDAC6i therapy in triple negative breast cancer and high grade serous ovarian cancer cells because TP53 altered cell lines have an increased dependency upon HDAC6. In western blot analysis of TNBC cell lines HDAC6 is upregulated compared to normal cells and further upregulated in cells mutated for BRCA1. The selective inhibition of HDAC6 with ricolinostat inhibited HDAC6 deacetylation of α-tubulin, resulting in a sustained accumulation of acetylated α-tubulin up to 24 hours. However, this did not translate to robust inhibition of HDAC6 protein function. Inhibition of cancer cell proliferation and migration required significantly higher and non-selective doses of ricolinostat than those required to eliminate its enzymatic activity. Molecular modelling of ricolinostat was performed to understand ricolinostat binding interactions with human HDAC6. Our data demonstrates the functional activity of both catalytic domains in living cells in which inhibition of both catalytic domains would be required for complete inhibition of HDAC6. Molecular dynamic simulations confirm that ricolinostat is capable of binding both catalytic domains and also indicates the potential for ricolinostat to bind multiple HDACs at higher concentrations. In conclusion, selective HAC6 inhibition has limited efficacy as a monotherapy in the treatment of solid tumours.
Original languageEnglish
Publication statusPublished - 2019
EventBACR - New Developments in Breast Cancer Research - from the Lab to the Clinic - The Sage, Newcastle, United Kingdom
Duration: 09 Oct 201911 Oct 2019
https://www.bacr.org.uk/event/new-developments-in-breast-cancer-research-from-the-lab-to-the-clinic

Conference

ConferenceBACR - New Developments in Breast Cancer Research - from the Lab to the Clinic
Country/TerritoryUnited Kingdom
CityNewcastle
Period09/10/201911/10/2019
Internet address

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