Epigenetic regulation of NOTCH1 and NOTCH3 by KMT2A inhibits glioma proliferation

Yin Cheng Huang, Sheng Jia Lin, Hung Yu Shih, Chung Han Chou, Hsiao Han Chu, Ching Chi Chiu, Chiou Hwa Yuh, Tu Hsueh Yeh, Yi Chuan Cheng

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Glioblastomas are among the most fatal brain tumors; however, the molecular determinants of their tumorigenic behavior are not adequately defined. In this study, we analyzed the role of KMT2A in the glioblastoma cell line U-87 MG. KMT2A knockdown promoted cell proliferation. Moreover, it increased the DNA methylation of NOTCH1 and NOTCH3 and reduced the expression of NOTCH1 and NOTCH3. NOTCH1 or NOTCH3 activation inhibited U-87 MG cell proliferation, whereas NOTCH1 and NOTCH3 inhibition by shRNAs induced cell proliferation, thus demonstrating the tumor-suppressive ability of NOTCH1 and NOTCH3 in U-87 MG cells. The induced cell proliferation caused by KMT2A knockdown could be nullified by using either constitutively active NOTCH1 or constitutively active NOTCH3. This result demonstrates that KMT2A positively regulates NOTCH1 and NOTCH3 and that this mechanism is essential for inhibiting the U-87 MG cell proliferation. The role of KMT2A knockdown in promoting tumor growth was further confirmed in vivo by transplanting U-87 MG cells into the brains of zebrafish larvae. In conclusion, we identified KMT2A-NOTCH as a negative regulatory cascade for glioblastoma cell proliferation, and this result provides important information for KMT2A- or NOTCH-targeted therapeutic strategies for brain tumors.

Original languageEnglish
Pages (from-to)63110-63120
Number of pages11
JournalOncotarget
Volume8
Issue number38
DOIs
Publication statusPublished - 2017

Fingerprint

Epigenomics
Glioma
Cell Proliferation
Glioblastoma
Brain Neoplasms
Aptitude
Zebrafish
DNA Methylation
Larva
Neoplasms
Cell Line
Brain
Growth

Keywords

  • Glioma
  • KMT2A
  • NOTCH
  • Zebrafish

ASJC Scopus subject areas

  • Oncology

Cite this

Huang, Y. C., Lin, S. J., Shih, H. Y., Chou, C. H., Chu, H. H., Chiu, C. C., ... Cheng, Y. C. (2017). Epigenetic regulation of NOTCH1 and NOTCH3 by KMT2A inhibits glioma proliferation. Oncotarget, 8(38), 63110-63120. https://doi.org/10.18632/oncotarget.18668

Epigenetic regulation of NOTCH1 and NOTCH3 by KMT2A inhibits glioma proliferation. / Huang, Yin Cheng; Lin, Sheng Jia; Shih, Hung Yu; Chou, Chung Han; Chu, Hsiao Han; Chiu, Ching Chi; Yuh, Chiou Hwa; Yeh, Tu Hsueh; Cheng, Yi Chuan.

In: Oncotarget, Vol. 8, No. 38, 2017, p. 63110-63120.

Research output: Contribution to journalArticle

Huang, YC, Lin, SJ, Shih, HY, Chou, CH, Chu, HH, Chiu, CC, Yuh, CH, Yeh, TH & Cheng, YC 2017, 'Epigenetic regulation of NOTCH1 and NOTCH3 by KMT2A inhibits glioma proliferation', Oncotarget, vol. 8, no. 38, pp. 63110-63120. https://doi.org/10.18632/oncotarget.18668
Huang, Yin Cheng ; Lin, Sheng Jia ; Shih, Hung Yu ; Chou, Chung Han ; Chu, Hsiao Han ; Chiu, Ching Chi ; Yuh, Chiou Hwa ; Yeh, Tu Hsueh ; Cheng, Yi Chuan. / Epigenetic regulation of NOTCH1 and NOTCH3 by KMT2A inhibits glioma proliferation. In: Oncotarget. 2017 ; Vol. 8, No. 38. pp. 63110-63120.
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