In planta gene targeting
Open Access
- 23 April 2012
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 109 (19), 7535-7540
- https://doi.org/10.1073/pnas.1202191109
Abstract
Purpose: DNA methylation in human papillomavirus–associated (HPV+) head and neck squamous cell carcinoma (HNSCC) may have importance for continuous expression of HPV oncogenes, tumor cell proliferation, and survival. Here, we determined activity of a global DNA-demethylating agent, 5-azacytidine (5-aza), against HPV+ HNSCC in preclinical models and explored it as a targeted therapy in a window trial enrolling patients with HPV+ HNSCC. Experimental Design: Sensitivity of HNSCC cells to 5-aza treatment was determined, and then 5-aza activity was tested in vivo using xenografted tumors in a mouse model. Finally, tumor samples from patients enrolled in a window clinical trial were analyzed to identify activity of 5-aza therapy in patients with HPV+ HNSCC. Results: Clinical trial and experimental data show that 5-aza induced growth inhibition and cell death in HPV+ HNSCC. 5-aza reduced expression of HPV genes, stabilized p53, and induced p53-dependent apoptosis in HNSCC cells and tumors. 5-aza repressed expression and activity of matrix metalloproteinases (MMP) in HPV+ HNSCC, activated IFN response in some HPV+ head and neck cancer cells, and inhibited the ability of HPV+ xenografted tumors to invade mouse blood vessels. Conclusions: 5-aza may provide effective therapy for HPV-associated HNSCC as an alternative or complement to standard cytotoxic therapy. Clin Cancer Res; 1–12. ©2017 AACR.Keywords
This publication has 45 references indexed in Scilit:
- Application of Gene Targeting to Designed Mutation Breeding of High-Tryptophan RicePlant Physiology, 2011
- Efficient design and assembly of custom TALEN and other TAL effector-based constructs for DNA targetingNucleic Acids Research, 2011
- Genome editing with engineered zinc finger nucleasesNature Reviews Genetics, 2010
- Genome editing in plant cells by zinc finger nucleasesTrends in Plant Science, 2010
- High frequency targeted mutagenesis in Arabidopsis thaliana using zinc finger nucleasesProceedings of the National Academy of Sciences, 2010
- High-frequency modification of plant genes using engineered zinc-finger nucleasesNature, 2009
- Protocol: Streamlined sub-protocols for floral-dip transformation and selection of transformants in Arabidopsis thalianaPlant Methods, 2009
- Two Unlinked Double-Strand Breaks Can Induce Reciprocal Exchanges in Plant Genomes via Homologous Recombination and Nonhomologous End JoiningGenetics, 2007
- Capture of genomic and T-DNA sequences during double-strand break repair in somatic plant cellsThe EMBO Journal, 1998
- Repair of genomic double‐strand breaks in somatic plant cells by one‐sided invasion of homologous sequencesThe Plant Journal, 1998