THE QUANTITATIVE EFFECTS OF EPIGENETIC INHIBITORS ON HISTONE PROTEOFORMS IN BREAST CANCER

Holt, Matthew; Wang, Tao; Young, Nicolas

Epigenetic modifications play a critical role in cancer identity, metastasis and drug response. Covalent modifications, such as phosphorylation, acetylation and methylation, of Histones (the nucleosome core proteins), are major pathways through which epigenetic modulation of the genome can influence cancer biology. Additionally, Histones have multiple sequence variants which play distinct roles dependent on cellular context, such as DNA repair, replication, and development. The combination of different histone variants and covalent modifications, creates a complex and dynamic protein landscape. Most studies fail to differentiate between histone variants or pairs of modifications on the same protein molecule. We have developed a method for rapidly quantifying histones by liquid chromatography mass spectrometry, where we can distinguish the exact histone variant and all its modifications, collectively known as the proteoform. We hypothesize that specific histone proteoforms play critical roles in cancer biology. Several novel potential drugs have been identified that specifically target epigenetic modifications, such as Bromodomain and Extra-Terminal motif (BET) inhibiting drugs. These show promise in treating triple negative breast cancer (TNBC) as well as many other types of cancer. However the exact mechanism of BET inhibitors has not yet been understood. In this study, we aim to quantify all histone proteoforms in breast cancer and the subsequent effects of BET inhibitors and other drugs.