TY - JOUR
T1 - Heterocyclic Analogs of Sulforaphane Trigger DNA Damage and Impede DNA Repair in Colon Cancer Cells
T2 - Interplay of HATs and HDACs
AU - Okonkwo, Adaobi
AU - Mitra, Joy
AU - Johnson, Gavin S.
AU - Li, Li
AU - Dashwood, Wan Mohaiza
AU - Hegde, Muralidhar L.
AU - Yue, Chen
AU - Dashwood, Roderick H.
AU - Rajendran, Praveen
N1 - Funding Information:
P.R., A.O., and R.H.D. were responsible for the concept and design of the studies. J.M. and M.H. performed DNA repair experiments. C.Y. synthesized and provided the SFN analogs. L.L. and G.S.J. performed PLA, immunofluorescence, and microscopy. A.O. performed cell-based mechanistic experiments, immunoblotting, and immunoprecipitation experiments. W.M.D. assisted with the animal experiments. P.R. and R.H.D. drafted, edited, and finalized the manuscript, with input from all co-authors. The authors thank Margie Moczygemba and Sevinj Iskandarova of the Flow Cytometry Core (Texas A&M Health Science Center, Houston, TX) for technical assistance. Christiane V. Löhr and Kay A. Fischer performed IHC on Pirc tissues (Oregon Veterinary Diagnostic Laboratory, Oregon State University, Corvallis, OR). This research was supported in part by NIH grants CA090890 and CA122959, as well as the John S. Dunn Foundation, Chancellor’s Research Initiative, for R.H.D., and R01 NS088645 for M.H.
Funding Information:
P.R., A.O., and R.H.D. were responsible for the concept and design of the studies. J.M. and M.H. performed DNA repair experiments. C.Y. synthesized and provided the SFN analogs. L.L. and G.S.J. performed PLA, immunofluorescence, and microscopy. A.O. performed cell-based mechanistic experiments, immunoblotting, and immunoprecipitation experiments. W.M.D. assisted with the animal experiments. P.R. and R.H.D. drafted, edited, and finalized the manuscript, with input from all co-authors. The authors thank Margie Moczygemba and Sevinj Iskandarova of the Flow Cytometry Core (Texas A&M Health Science Center, Houston, TX) for technical assistance. Christiane V. Löhr and Kay A. Fischer performed IHC on Pirc tissues (Oregon Veterinary Diagnostic Laboratory, Oregon State University, Corvallis, OR). This research was supported in part by NIH grants CA090890 and CA122959, as well as the John S. Dunn Foundation, Chancellor's Research Initiative, for R.H.D., and R01 NS088645 for M.H.
Publisher Copyright:
© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2018/9
Y1 - 2018/9
N2 - 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.
AB - 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.
KW - C-terminal binding protein (CtBP) interacting protein
KW - DNA damage
KW - DNA repair
KW - colon cancer
KW - histone acetyltransferase
KW - histone deacetylase
KW - sulforaphane analogs
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U2 - 10.1002/mnfr.201800228
DO - 10.1002/mnfr.201800228
M3 - Article
C2 - 29924908
AN - SCOPUS:85050884281
SN - 1613-4125
VL - 62
JO - Molecular Nutrition and Food Research
JF - Molecular Nutrition and Food Research
IS - 18
M1 - 1800228
ER -