Inhibition of the Histone H3K27 Demethylase UTX Enhances Tumor Cell Radiosensitivity

Molecular Cancer Therapeutics
Barbara H RathPhilip Tofilon

Abstract

The processes mediating the repair of DNA double-strand breaks (DSB) are critical determinants of radiosensitivity and provide a source of potential targets for tumor radiosensitization. Among the events required for efficient DSB repair are a variety of post-translational histone modifications, including methylation. Because trimethylation of histone H3 on lysine 27 (H3K27me3) has been associated with chromatin condensation, which can influence DSB repair, we determined the effects of radiation on H3K27me3 levels in tumor and normal cell lines. Irradiation of tumor cells resulted in a rapid loss of H3K27me3, which was prevented by the siRNA-mediated knockdown of the H3K27 demethylase UTX. Knockdown of UTX also enhanced the radiosensitivity of each tumor cell line. Treatment of tumor cells with the H3K27 demethylase inhibitor GSKJ4 immediately before irradiation prevented the radiation-induced decrease in H3K27me3 and enhanced radiosensitivity. As determined by neutral comet analysis and γH2AX expression, this GSKJ4 treatment protocol inhibited the repair of radiation-induced DSBs. Consistent with in vitro results, treatment of mice bearing leg tumor xenografts with GSKJ4 significantly enhance radiation-induce tumor growth dela...Continue Reading

References

Sep 9, 1999·The Journal of Cell Biology·E P RogakouW M Bonner
Sep 28, 2002·Nature·Alexander W BirdMichael F Christman
Nov 5, 2004·Nature·Yentram HuyenThanos D Halazonetis
Dec 4, 2004·International Journal of Cancer. Journal International Du Cancer·Kevin CamphausenPhilip J Tofilon
Feb 27, 2007·Cell·Tony Kouzarides
Nov 16, 2007·Proceedings of the National Academy of Sciences of the United States of America·Sunhwa HongKai Ge
May 14, 2008·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·Eva BártováStanislav Kozubek
Sep 4, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Prakash ChinnaiyanPhilip J Tofilon
Oct 23, 2009·Nature·Stephen P Jackson, Jiri Bartek
Jan 30, 2010·Journal of Cellular Physiology·Qianzheng Zhu, Altaf A Wani
Oct 13, 2010·Proceedings of the National Academy of Sciences of the United States of America·Danny M ChouStephen J Elledge
Dec 29, 2010·Proceedings of the National Academy of Sciences of the United States of America·Sheema FnuRobert Hromas
Mar 21, 2012·Nature Immunology·Laurence ZitvogelGuido Kroemer
Mar 19, 2013·Cell·Brendan D Price, Alan D D'Andrea
Aug 3, 2013·Cell Cycle·Stuart CampbellMichael J Hendzel
Jun 14, 2014·Proceedings of the National Academy of Sciences of the United States of America·Marina K AyrapetovBrendan D Price
Aug 15, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·David KarnakMeredith A Morgan
Oct 4, 2014·Nature·Bo HeinemannKristian Helin
Jul 22, 2015·International Journal of Radiation Oncology, Biology, Physics·Andra V KrauzeKevin Camphausen
Dec 3, 2015·Journal of Molecular Biology·Ozge Gursoy-YuzugulluBrendan D Price
Feb 6, 2016·Nature Medicine·Kimberly H Kim, Charles W M Roberts
Mar 16, 2016·International Journal of Radiation Oncology, Biology, Physics·Kyle C CuneoTheodore S Lawrence

❮ Previous
Next ❯

Citations

Mar 22, 2019·The Cancer Journal·Mohammad K KhanStephen J Kron
Jan 23, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Mayukh BiswasAmitava Sengupta
May 8, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Simone PippaRodolfo Negri
Apr 21, 2020·Essays in Biochemistry·Xin Yi Tan, Michael S Y Huen
Mar 9, 2021·Frontiers in Cell and Developmental Biology·Qin PengYongzhong Wu
Mar 21, 2021·Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology·Ariana Cabrera-LiconaElena Aréchaga-Ocampo
Apr 17, 2021·Frontiers in Genetics·Elena Di NisioRodolfo Negri
Jun 5, 2021·Mutation Research. Reviews in Mutation Research·Yuchuan Zhou, Chunlin Shao

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

© 2022 Meta ULC. All rights reserved