Normal cell function is dependent on the proper maintenance of chromatin 
structure. Regulation of chromatin structure is controlled by histone 
modifications that directly influence chromatin architecture and genome 
function. Specifically, the histone deacetylase (HDAC) family of proteins 
modulate chromatin compaction and are commonly dysregulated in many tumors, 
including colorectal cancer (CRC). However, the role of HDAC proteins in early 
colorectal carcinogenesis has not been previously reported. We found HDAC1, 
HDAC2, HDAC3, HDAC5, and HDAC7 all to be up-regulated in the field of human CRC. 
Furthermore, we observed that HDAC2 up-regulation is one of the earliest events 
in CRC carcinogenesis and observed this in human field carcinogenesis, the 
azoxymethane-treated rat model, and in more aggressive colon cancer cell lines. 
The universality of HDAC2 up-regulation suggests that HDAC2 up-regulation is a 
novel and important early event in CRC, which may serve as a biomarker. HDAC 
inhibitors (HDACIs) interfere with tumorigenic HDAC activity; however, the 
precise mechanisms involved in this process remain to be elucidated. We 
confirmed that HDAC inhibition by valproic acid (VPA) targeted the more 
aggressive cell line. Using nuclease digestion assays and transmission electron 
microscopy imaging, we observed that VPA treatment induced greater changes in 
chromatin structure in the more aggressive cell line. Furthermore, we used the 
novel imaging technique partial wave spectroscopy (PWS) to quantify nanoscale 
alterations in chromatin. We noted that the PWS results are consistent with the 
biological assays, indicating a greater effect of VPA treatment in the more 
aggressive cell type. Together, these results demonstrate the importance of HDAC 
activity in early carcinogenic events and the unique role of higher-order 
chromatin structure in determining cell tumorigenicity.