Chromatin structure plays a critical role in maintaining proper gene expression. Epigenetic changes in the form of covalent modifications on histones including acetylation help regulate chromatin structure and gene expression. One group of enzymes, the histone deacetylases (HDACs) catalyze the removal of acetyl groups from histones which generally leads to gene repression. Since cancer can be caused by aberrant changes in the expression of genes that control cell growth, HDACs have become important targets of chemotherapeutics. Histone deacetylase inhibitors are currently being tested in clinical trials to treat several types of cancers, including breast cancer. These drugs are effective at preferentially halting growth of cancer cells over normal cells. However, the HDAC inhibitors currently in use target the catalytic sites of HDACs and do not discriminate among the several structurally similar HDACs in humans. Thus these HDAC inhibitors exhibit undesirable side effects due to their lack of specificity for individual HDACs. Individual HDACs reside in multi-subunit protein complexes, and a few known examples show that some of these HDAC-associated proteins are associated with and required for the catalytic activity of a particular HDAC. Therefore, as an alternative to inhibiting the HDAC enzymes themselves, inhibiting HDAC- interacting proteins should provide just as effective, but more specific treatment. This proposal will identify and functionally characterize proteins specifically associated with either HDAC1 or HDAC3 that can control breast cancer proliferation through modulation of their specific associated HDAC's activity. ? ? Specific Aims: 1. Perform proteomics analysis to identify proteins associated with HDAC1 and HDACS in human cells. Biochemically identify the subunit composition and the number of distinct complex(es) the HDACs and their differentially associated proteins reside in. 2. Identify which HDAC-interacting proteins are important for HDAC activity and determine how HDAC1- and HDACS-associated proteins affect the activity and integrity of their associated HDAC complex. 3. Target HDAC1- and 3-containing complexes in invasive breast cancer cells using siRNAs and identify which proteins, when abrogated, halt cancer cell growth. Relevance to Public Health: Many current anti-cancer drugs show unwanted toxic side effects in patients due to poor specificity of these drugs for their targets. This proposal seeks to find more specific protein targets for chemotherapeutics which should decrease the toxicity of these drugs. ? ? ?
| Sardiu, Mihaela E; Smith, Karen T; Groppe, Brad D et al. (2014) Suberoylanilide hydroxamic acid (SAHA)-induced dynamics of a human histone deacetylase protein interaction network. Mol Cell Proteomics 13:3114-25 |
| Smith, Karen T; Sardiu, Mihaela E; Martin-Brown, Skylar A et al. (2012) Human family with sequence similarity 60 member A (FAM60A) protein: a new subunit of the Sin3 deacetylase complex. Mol Cell Proteomics 11:1815-28 |
| Smith, Karen T; Martin-Brown, Skylar A; Florens, Laurence et al. (2010) Deacetylase inhibitors dissociate the histone-targeting ING2 subunit from the Sin3 complex. Chem Biol 17:65-74 |
