FUNCTION OF VERTICILLIN A IN SUPPRESSION OF MDSC AND CRC STEM CELLS

Project Summary The current 5-year survival rate for patients with metastatic colorectal cancer (CRC) is only about 8%.The vast majority of CRC mortality is due to cancer cell resistance to existing therapeutic agents. Therefore,development of novel agents that can suppress drug-resistant metastatic CRC is in urgent need. We havepurified from wild mushroom a compound with potent anti-tumor activity. This compound was identified asVerticillin A. We demonstrated that Verticillin A modifies the BNIP3 promoter chromatin histone structure toover-ride the silencing effect of DNA methylation to activate BNIP3 transcription in metastatic human CRCcells. Interestingly, our preliminary studies revealed that Verticillin A is effective in suppression of drug-resistant CRC stem cell growth. Our long-term objective is to develop Verticillin A as a therapeutic agent fortreatment of human patients with metastatic CRC. The objectives of this project are to elucidate theunderlying molecular mechanisms of Verticillin A action and to determine whether Verticillin A caneffectively suppress MDSC and drug-resistant CRC stem cells in vivo. We propose to pursue the followingthree aims: 1) determine the network of DNA and H3K9 methylation in the BNIP3 promoter chromatin thatmediates BNIP transcriptional repression in human CRC cells; 2) test the hypothesis that Verticillin Atargets histone methylation to activate BNIP3 transcription and suppress spontaneous metastasis of 5-FU-resistant CRC stem cells in vivo; and 3) test the hypothesis that Verticillin A and 5-FU cooperate to induceMDSC apoptosis and suppress MDSC accumulation. Successful completion of these proposed studies hasthe potential to develop Verticllin A as an effective drug for treatment of human patients with 5-FU-resistantmetastatic colorectal cancer.