Radiosensitization by histone H3 demethylase inhibition in diffuse intrinsic pontine glioma

Hiroaki Katagi, Nundia Louis, Dusten Unruh, Takahiro Sasaki, Xingyao He, Ali Zhang, Quanhong Ma, Andrea Piunti, Yosuke Shimazu, Jonathan B. Lamano, Angel M. Carcaboso, Xiao Tian, Andrei Seluanov, Vera Gorbunova, Kathryn L. Laurie, Akihide Kondo, Nitin R. Wadhwani, Rishi Lulla, Stewart Goldman, Sriram VennetiOren J. Becher, Lihua Zou, Ali Shilatifard, Rintaro Hashizume

Research output: Contribution to journalArticle

Abstract

Purpose: Radiotherapy (RT) has long been and remains the only treatment option for diffuse intrinsic pontine glioma (DIPG). However, all patients show evidence of disease progression within months of completing RT. No further clinical benefit has been achieved using alternative radiation strategies. Here, we tested the hypothesis that histone demethylase inhibition by GSK-J4 enhances radiationinduced DNA damage, making it a potential radiosensitizer in the treatment of DIPG. Experimental Design: Weevaluated the effects of GSK-J4 on genes associated with DNA double-strand break (DSB) repair in DIPG cells by RNA sequence, ATAC sequence, and quantitative real-time PCR. Radiation-induced DNA DSB repair was analyzed by immunocytochemistry of DSB markers γH2AX and 53BP1, DNA-repair assay, and cell-cycle distribution. Clonogenic survival assay was used to determine the effect of GSK-J4 on radiation response of DIPG cells. In vivo response to radiation monotherapy and combination therapy of RT and GSK-J4 was evaluated in patient-derived DIPG xenografts. Results: GSK-J4 significantly reduced the expression of DNA DSB repair genes and DNA accessibility in DIPG cells. GSK-J4 sustained high levels of γH2AX and 53BP1 in irradiated DIPG cells, thereby inhibiting DNADSB repair through homologous recombination pathway. GSK-J4 reduced clonogenic survival and enhanced radiation effect in DIPG cells. In vivo studies revealed increased survival of animals treated with combination therapy of RT and GSK-J4 compared with either monotherapy. Conclusions: Together, these results highlight GSK-J4 as a potential radiosensitizer and provide a rationale for developing combination therapy with radiation in the treatment of DIPG.

Original languageEnglish
Pages (from-to)5572-5583
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number18
DOIs
Publication statusPublished - Sep 15 2019
Externally publishedYes

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Histone Demethylases
Glioma
Histones
Radiotherapy
Double-Stranded DNA Breaks
Radiation
DNA Repair
Therapeutics
GSK-J4
Recombinational DNA Repair
Survival
Radiation Effects
Heterografts
Genes
DNA Damage
Disease Progression
Real-Time Polymerase Chain Reaction
Cell Cycle
Research Design
Immunohistochemistry

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Katagi, H., Louis, N., Unruh, D., Sasaki, T., He, X., Zhang, A., ... Hashizume, R. (2019). Radiosensitization by histone H3 demethylase inhibition in diffuse intrinsic pontine glioma. Clinical Cancer Research, 25(18), 5572-5583. https://doi.org/10.1158/1078-0432.CCR-18-3890

Radiosensitization by histone H3 demethylase inhibition in diffuse intrinsic pontine glioma. / Katagi, Hiroaki; Louis, Nundia; Unruh, Dusten; Sasaki, Takahiro; He, Xingyao; Zhang, Ali; Ma, Quanhong; Piunti, Andrea; Shimazu, Yosuke; Lamano, Jonathan B.; Carcaboso, Angel M.; Tian, Xiao; Seluanov, Andrei; Gorbunova, Vera; Laurie, Kathryn L.; Kondo, Akihide; Wadhwani, Nitin R.; Lulla, Rishi; Goldman, Stewart; Venneti, Sriram; Becher, Oren J.; Zou, Lihua; Shilatifard, Ali; Hashizume, Rintaro.

In: Clinical Cancer Research, Vol. 25, No. 18, 15.09.2019, p. 5572-5583.

Research output: Contribution to journalArticle

Katagi, H, Louis, N, Unruh, D, Sasaki, T, He, X, Zhang, A, Ma, Q, Piunti, A, Shimazu, Y, Lamano, JB, Carcaboso, AM, Tian, X, Seluanov, A, Gorbunova, V, Laurie, KL, Kondo, A, Wadhwani, NR, Lulla, R, Goldman, S, Venneti, S, Becher, OJ, Zou, L, Shilatifard, A & Hashizume, R 2019, 'Radiosensitization by histone H3 demethylase inhibition in diffuse intrinsic pontine glioma', Clinical Cancer Research, vol. 25, no. 18, pp. 5572-5583. https://doi.org/10.1158/1078-0432.CCR-18-3890
Katagi, Hiroaki ; Louis, Nundia ; Unruh, Dusten ; Sasaki, Takahiro ; He, Xingyao ; Zhang, Ali ; Ma, Quanhong ; Piunti, Andrea ; Shimazu, Yosuke ; Lamano, Jonathan B. ; Carcaboso, Angel M. ; Tian, Xiao ; Seluanov, Andrei ; Gorbunova, Vera ; Laurie, Kathryn L. ; Kondo, Akihide ; Wadhwani, Nitin R. ; Lulla, Rishi ; Goldman, Stewart ; Venneti, Sriram ; Becher, Oren J. ; Zou, Lihua ; Shilatifard, Ali ; Hashizume, Rintaro. / Radiosensitization by histone H3 demethylase inhibition in diffuse intrinsic pontine glioma. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 18. pp. 5572-5583.
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T1 - Radiosensitization by histone H3 demethylase inhibition in diffuse intrinsic pontine glioma

AU - Katagi, Hiroaki

AU - Louis, Nundia

AU - Unruh, Dusten

AU - Sasaki, Takahiro

AU - He, Xingyao

AU - Zhang, Ali

AU - Ma, Quanhong

AU - Piunti, Andrea

AU - Shimazu, Yosuke

AU - Lamano, Jonathan B.

AU - Carcaboso, Angel M.

AU - Tian, Xiao

AU - Seluanov, Andrei

AU - Gorbunova, Vera

AU - Laurie, Kathryn L.

AU - Kondo, Akihide

AU - Wadhwani, Nitin R.

AU - Lulla, Rishi

AU - Goldman, Stewart

AU - Venneti, Sriram

AU - Becher, Oren J.

AU - Zou, Lihua

AU - Shilatifard, Ali

AU - Hashizume, Rintaro

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N2 - Purpose: Radiotherapy (RT) has long been and remains the only treatment option for diffuse intrinsic pontine glioma (DIPG). However, all patients show evidence of disease progression within months of completing RT. No further clinical benefit has been achieved using alternative radiation strategies. Here, we tested the hypothesis that histone demethylase inhibition by GSK-J4 enhances radiationinduced DNA damage, making it a potential radiosensitizer in the treatment of DIPG. Experimental Design: Weevaluated the effects of GSK-J4 on genes associated with DNA double-strand break (DSB) repair in DIPG cells by RNA sequence, ATAC sequence, and quantitative real-time PCR. Radiation-induced DNA DSB repair was analyzed by immunocytochemistry of DSB markers γH2AX and 53BP1, DNA-repair assay, and cell-cycle distribution. Clonogenic survival assay was used to determine the effect of GSK-J4 on radiation response of DIPG cells. In vivo response to radiation monotherapy and combination therapy of RT and GSK-J4 was evaluated in patient-derived DIPG xenografts. Results: GSK-J4 significantly reduced the expression of DNA DSB repair genes and DNA accessibility in DIPG cells. GSK-J4 sustained high levels of γH2AX and 53BP1 in irradiated DIPG cells, thereby inhibiting DNADSB repair through homologous recombination pathway. GSK-J4 reduced clonogenic survival and enhanced radiation effect in DIPG cells. In vivo studies revealed increased survival of animals treated with combination therapy of RT and GSK-J4 compared with either monotherapy. Conclusions: Together, these results highlight GSK-J4 as a potential radiosensitizer and provide a rationale for developing combination therapy with radiation in the treatment of DIPG.

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