KDM1 is a novel therapeutic target for the treatment of gliomas

Gangadhara R. Sareddy, Binoj C. Nair, Samaya K. Krishnan, Vijay K. Gonugunta, Quanguang Zhang, Takayoshi Suzuki, Naoki Miyata, Andrew J. Brenner, Darrell W Brann, Ratna K. Vadlamudi

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Glioma development is a multistep process, involving alterations in genetic and epigenetic mechanisms. Understanding the mechanisms and enzymes that promote epigenetic changes in gliomas are urgently needed to identify novel therapeutic targets. We examined the role of histone demethylase KDM1 in glioma progression. KDM1 was overexpressed in gliomas and its expression positively correlated with histological malignancy. Knockdown of KDM1 expression or its pharmacological inhibition using pargyline or NCL-1 significantly reduced the proliferation of glioma cells. Inhibition of KDM1 promoted up regulation of the p53 target genes p21 and PUMA. Patient-derived primary GBM cells expressed high levels of KDM1 and pharmacological inhibition of KDM1 decreased their proliferation. Further, KDM1 inhibition reduced the expression of stemness markers CD133 and nestin in GBM cells. Mouse xenograft assays revealed that inhibition of KDM1 significantly reduced glioma xenograft tumor growth. Inhibition of KDM1 increased levels of H3K4-me2 and H3K9- Ac histone modifications, reduced H3K9-me2 modification and promoted expression of p53 target genes (p21 and PUMA), leading to apoptosis of glioma xenograft tumors. Our results suggest that KDM1 is overexpressed in gliomas and could be a potential therapeutic target for the treatment of gliomas.

Original languageEnglish (US)
Pages (from-to)18-28
Number of pages11
JournalOncotarget
Volume4
Issue number1
DOIs
StatePublished - Jan 1 2013

Fingerprint

Glioma
Heterografts
Therapeutics
p53 Genes
Epigenomics
Histone Code
Histone Demethylases
Pharmacology
Pargyline
Nestin
Neoplasms
Up-Regulation
Cell Proliferation
Apoptosis
Enzymes
Growth

Keywords

  • Epigenetics
  • GBM
  • Gliomas
  • KDM1
  • P53

ASJC Scopus subject areas

  • Oncology

Cite this

Sareddy, G. R., Nair, B. C., Krishnan, S. K., Gonugunta, V. K., Zhang, Q., Suzuki, T., ... Vadlamudi, R. K. (2013). KDM1 is a novel therapeutic target for the treatment of gliomas. Oncotarget, 4(1), 18-28. https://doi.org/10.18632/oncotarget.725

KDM1 is a novel therapeutic target for the treatment of gliomas. / Sareddy, Gangadhara R.; Nair, Binoj C.; Krishnan, Samaya K.; Gonugunta, Vijay K.; Zhang, Quanguang; Suzuki, Takayoshi; Miyata, Naoki; Brenner, Andrew J.; Brann, Darrell W; Vadlamudi, Ratna K.

In: Oncotarget, Vol. 4, No. 1, 01.01.2013, p. 18-28.

Research output: Contribution to journalArticle

Sareddy, GR, Nair, BC, Krishnan, SK, Gonugunta, VK, Zhang, Q, Suzuki, T, Miyata, N, Brenner, AJ, Brann, DW & Vadlamudi, RK 2013, 'KDM1 is a novel therapeutic target for the treatment of gliomas', Oncotarget, vol. 4, no. 1, pp. 18-28. https://doi.org/10.18632/oncotarget.725
Sareddy GR, Nair BC, Krishnan SK, Gonugunta VK, Zhang Q, Suzuki T et al. KDM1 is a novel therapeutic target for the treatment of gliomas. Oncotarget. 2013 Jan 1;4(1):18-28. https://doi.org/10.18632/oncotarget.725
Sareddy, Gangadhara R. ; Nair, Binoj C. ; Krishnan, Samaya K. ; Gonugunta, Vijay K. ; Zhang, Quanguang ; Suzuki, Takayoshi ; Miyata, Naoki ; Brenner, Andrew J. ; Brann, Darrell W ; Vadlamudi, Ratna K. / KDM1 is a novel therapeutic target for the treatment of gliomas. In: Oncotarget. 2013 ; Vol. 4, No. 1. pp. 18-28.
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