Project Summary/Abstract
The genetics behind colon cancer is now well described, but even among tumors with identical genetic
mutations, tumor heterogeneity remains problematic in the clinical setting. Epigenomics, including histone post-
translational modifications (PTMs), can modulate gene expression and explain heterogeneity. Epigenomic
regulators have gained attention as candidates for targeted cancer therapy. However, there are still large
gaps in understanding the role of epigenomics in colon cancer.
This proposal’s primary objective is to uncover the roles of KAT2A and KAT2B in normal intestinal epithelium
homeostasis and colon cancer. These genes encode histone lysine acetyltransferase enzymes, whose
functions have not yet been elucidated in colon cancer. KAT2A is normally expressed in intestinal stem and
proliferative cells, while KAT2B is enriched in differentiated epithelium. In tumors, KAT2A levels are elevated,
while KAT2B levels are reduced. I hypothesize that KAT2A catalyzes histone PTMs to promote proliferative
gene expression and drive colon tumorigenesis, while KAT2B promotes differentiation gene expression and
suppresses colon tumorigenesis. Alternatively, these lysine acetyltransferases could function redundantly. The
rationale for this study is based on preliminary data showing that KAT2A and KAT2B are differentially
expressed in normal versus cancerous colon tissue and the observation that they can catalyze histone acetyl
as well as non-acetyl histone modifications. Importantly, these factors have not been functionally tested in vivo
in the intestine. Aim 1 will use novel genetic mouse models to assess the effects of KAT2A/KAT2B knockout
on intestinal homeostasis and colon cancer by employing histology studies, organoid assays, tumor
quantification, and qRT-PCR screening. Aim 2 will use histone PTM mass spectrometry analysis, RNA-seq,
and ChIP-seq to determine 1) important acetyl and non-acetyl histone PTMs catalyzed by KAT2A/KAT2B and
2) how the binding sites of KAT2A/KAT2B and their PTMs correlate with changes in the transcriptome.
The significance of this proposal is that it will improve our understanding of epigenetic mechanisms in colon
cancer and introduces two candidate genes, KAT2A and KAT2B, to target in colon cancer. With the training
plan devised by Dr. Michael Verzi, the applying fellow will 1) gain expertise in genetics and cancer, 2) develop
effective scientific communication skills, and 3) prepare to lead a lab as an independent translational cancer
researcher within a nurturing, resourceful, and collaborative environment at Rutgers University.