Adaobi Okonkwo1, Joy Mitra2, Gavin S Johnson1, Li Li1, Wan Mohaiza Dashwood1, Muralidhar L Hegde2,3, Chen Yue4, Roderick H Dashwood1,5,6,7, Praveen Rajendran1. 1. Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M Health Science Center, Texas A&M College of Medicine, Houston, TX, USA, 77030. 2. Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX, USA, 77030. 3. Weill Cornell Medical College of Cornell University, NY, USA, 10065. 4. The State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China, 300071. 5. Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA, 77030. 6. Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA, 77843. 7. Department of Molecular and Cellular Medicine, Texas A&M College of Medicine, College Station, TX, USA, 77843.
Abstract
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.
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.
Authors: Ahmet M Ulusan; Praveen Rajendran; Wan Mohaiza Dashwood; Omer F Yavuz; Sabeeta Kapoor; Trace A Gustafson; Michelle I Savage; Powel H Brown; Shizuko Sei; Altaf Mohammed; Eduardo Vilar; Roderick H Dashwood Journal: Cancer Prev Res (Phila) Date: 2020-12-04
Authors: Marek Samec; Alena Liskova; Lenka Koklesova; Veronika Mestanova; Maria Franekova; Monika Kassayova; Bianka Bojkova; Sona Uramova; Pavol Zubor; Katarina Janikova; Jan Danko; Samson Mathews Samuel; Dietrich Büsselberg; Peter Kubatka Journal: Biomolecules Date: 2019-12-05