Histone deacetylases (HDAC) are involved in carcinogenesis through their regulation of cell proliferation, differentiation, and survival. The inhibitors of HDAC exhibit profound synergistic effects in cancer treatment when combined with other anticancer drugs. However, the molecular mechanisms underlying this synergy are not fully understood. Here, we show that HDAC1 increases the resistance of cancer cells to oxidative stress by negatively regulating the expression of thioredoxin binding protein 2 (TBP-2). We found that the recruitment of HDAC1 to the TBP-2 promoter is mediated by a protein complex consisting of RET finger protein (RFP; also called TRIM27) and the trimeric transcription factor NF-Y. Accordingly, RNA interference-mediated depletion of RFP led to the disruption of the protein complex and a marked increase in the sensitivity of cancer cells to cisplatin, a potent inducer of oxidative stress. Furthermore, high levels of RFP expression correlated with down-regulation of TBP-2 in human colon cancers and were associated with poor clinical outcome. These findings reveal the diverse cancer-promoting activities of HDAC1 and identify RFP as a key regulator that provides cancer cells with resistance to anticancer drugs.