Heterocyclic Analogs of Sulforaphane Trigger DNA Damage and Impede DNA Repair in Colon Cancer Cells: Interplay of HATs and HDACs.
SCOPE
DNA repair inhibitors have broad clinical applications in tumor types with DNA repair defects, including colorectal cancer (CRC). Structural analogs of the anticancer agent sulforaphane (SFN) were investigated as modifiers of histone deacetylase (HDAC) and histone acetyltransferase (HAT) activity, and for effects on DNA damage/repair pertinent to human CRC.


METHODS AND RESULTS
In the polyposis in rat colon (Pirc) model, single oral administration of SFN and structurally related long-chain isothiocyanates (ITCs) decreased histone deacetylase 3 (HDAC3) expression and increased pH2AX levels markedly in adenomatous colon polyps, extending prior observations on HDAC3 inhibition/turnover in cell-based assays. Colon cancer cells at a high initial plating density had diminished cytotoxicity from SFN, whereas novel tetrazole-containing heterocyclic analogs of SFN retained their efficacy. The potent SFN analogs triggered DNA damage, cell cycle arrest, apoptosis, and loss of a key DNA repair regulator, C-terminal binding protein (CtBP) interacting protein (CtIP). These SFN analogs also altered HAT/HDAC activities and histone acetylation status, lowered the expression of HDAC3, P300/CBP-associated factor (PCAF) and lysine acetyltransferase 2A (KAT2A/GCN5), and attenuated homologous recombination (HR)/non-homologous end joining (NHEJ) repair activities in colon cancer cells.


CONCLUSION
Novel tetrazole-containing heterocyclic analogs of SFN provide a new avenue for chemosensitization in colon cancer cells via modulation of HAT/HDAC activities and associated DNA damage/repair signaling pathways.
['Okonkwo|Adaobi|A|', 'Mitra|Joy|J|', 'Johnson|Gavin S|GS|', 'Li|Li|L|', 'Dashwood|Wan Mohaiza|WM|', 'Hegde|Muralidhar L|ML|', 'Yue|Chen|C|', 'Dashwood|Roderick H|RH|', 'Rajendran|Praveen|P|']
D000818:Animals D017209:Apoptosis D001937:Brassica D059447:Cell Cycle Checkpoints D045744:Cell Line, Tumor D003110:Colonic Neoplasms D004249:DNA Damage D004260:DNA Repair D005260:Female D005786:Gene Expression Regulation D045325:HCT116 Cells D057809:HEK293 Cells D051548:Histone Acetyltransferases D006655:Histone Deacetylases D006801:Humans D017879:Isothiocyanates D008297:Male D009149:Mustard Plant D051381:Rats D011916:Rats, Inbred F344 D013454:Sulfoxides D013777:Tetrazoles D014675:Vegetables D031228:Wasabia D050880:p300-CBP Transcription Factors
DNA damage DNA repair colon cancer histone deacetylase histone acetyltransferase C-terminal binding protein (CtBP) interacting protein sulforaphane analogs