Histone deacetylase inhibitors (HDACi), a diverse class of compounds that inhibit the activity of lysine deacetylases (KDAC), have shown promise as cancer therapeutics.  Although several HDACi have been introduced into clinical trials and some others approved for use in treatment of cancers, how these inhibitors mediate their effect is not well understood.  HDACi were initially considered for cancer therapy due to the observation that cancer cells exhibit global hypoacetylation of histones, leading to decreased transcription of tumor suppressor genes and decreased cell cycle control.  While lysine acetylation is frequently associated with histones, this modification is beginning to be appreciated as a regulator of other proteins including proteins known to be involved in cancer.  We investigated how three different HDACi alter proliferation in the non-small cell lung cancrinoma (NSCLC) cell line A549.  The inhibitors used were:   Trichostatin A (TSA), which inhibits zinc-dependent Class I and II histone deacetylases, Nicotinamide (NAM), which inhibits NAD+-dependent Class III histone deacetylases, and CUDC-101, a dual inhibitor of Class I/II histone deacetylases and epidermal growth factor receptor (EGFR).  We found that TSA rapidly decreased proliferation.  Additionally, CUDC-101 decreased proliferation, although to a lesser extent than TSA.  In contrast, NAM did not decrease A549 proliferation.  To investigate how HDACi were mediating these effects on proliferation, we took an unbiased mass spectrometry approach to assess the acetylation status of different proteins following treatment. Understanding how HDACi affect the activities of individual proteins is essential to determining the mechanisms through which HDACi elicit their effects on cancer cells, and gaining insight into causes of resistance to treatment in NSCLC.

Effects of histone deacetylase inhibitors on the non-small cell lung carcinoma cell line A549

243rd National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.