Colorectal cancer (CRC) is the most common cause of deaths in the West. Despite many therapeutic opportunities, drug resistance or recurrence has significant rates among patients. Nearly 50% of CRC patients develop metastases. Therefore, sensitive biomarker and effective treatments with minimal toxicity are needed. Genetic and epigenetic alterations play major roles in initiation, development, and chemoresistance of CRC. Histone deacetylase2 (HDAC2) over-expression is well-known in CRC. Many studies have associated HDAC2 over-expression and TP53 mutations with late stages of metastatic CRC (mCRC). However, the relationship between HDAC2 expression level and TP53 status and mCRC drug resistance is unclear. Here, I have investigated HDAC2 role in drug resistance and assessed the synergistic effects of DNA chemotherapeutics agents and HDAC inhibitors (HDACIs) on TP53 status in mCRC cell lines. I have shown for the first time that in mutated p53 mCRC cells (Sw480 and HT-29) the steady-state level of HDAC2 is low compared to wild-type p53 cells (HCT116 p53+/+). I have also found that increase in HDAC2 expression level in the highly resistant cell line HT-29 enhances drug resistance and its depletion by shRNA sensitises HT-29 to 5Fluorouracil (5FU) or Oxaliplatin (Oxa). The combined treatment of suberoylanilide hydroxamic acid (SAHA)/5FU and SAHA/Oxa was able to reduced HDAC2 expression level and induced mitotic cell death. However, SAHA/Doxorubicin combined treatment induced cell death in wild-type p53 (HCT116 p53+/+), null p53 (HCT116 p53-/-), and SW480 cell lines. This cell death associated with decrease in HDAC2 level. I have shown the association between sensitivity to treatment and reduction of HDAC2 level via bioluminescence imaging in combination with liposomal-encapsulated SAHA/Doxorubicin delivery to monitor tumour growth. I have observed a significant decrease in tumour growth and HADC2 level. Therefore, I suggest that unlike mutated p53, HDAC2 could be an epigenetic prognostic biomarker to predict therapeutic response in mCRC.