Skip to main content

KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation.

Publication ,  Journal Article
Guo, C; Chen, LH; Huang, Y; Chang, C-C; Wang, P; Pirozzi, CJ; Qin, X; Bao, X; Greer, PK; McLendon, RE; Yan, H; Keir, ST; Bigner, DD; He, Y
Published in: Oncotarget
November 2013

KMT2D (lysine (K)-specific methyltransferase 2D), formerly named MLL2 (myeloid/lymphoid or mixed-lineage leukemia 2, also known as ALR/MLL4), is a histone methyltransferase that plays an important role in regulating gene transcription. In particular, it targets histone H3 lysine 4 (H3K4), whose methylations serve as a gene activation mark. Recently, KMT2D has emerged as one of the most frequently mutated genes in a variety of cancers and in other human diseases, including lymphoma, medulloblastoma, gastric cancer, and Kabuki syndrome. Mutations in KMT2D identified thus far point to its loss-of-function in pathogenesis and suggest its role as a tumor suppressor in various tissues. To determine the effect of a KMT2D deficiency on neoplastic cells, we used homologous recombination- and nuclease-mediated gene editing approaches to generate a panel of isogenic colorectal and medulloblastoma cancer cell lines that differ with respect to their endogenous KMT2D status. We found that a KMT2D deficiency resulted in attenuated cancer cell proliferation and defective cell migration. Analysis of histone H3 modifications revealed that KMT2D was essential for maintaining the level of global H3K4 monomethylation and that its enzymatic SET domain was directly responsible for this function. Furthermore, we found that a majority of KMT2D binding sites are located in regions of potential enhancer elements. Together, these findings revealed the role of KMT2D in regulating enhancer elements in human cells and shed light on the tumorigenic role of its deficiency. Our study supports that KMT2D has distinct roles in neoplastic cells, as opposed to normal cells, and that inhibiting KMT2D may be a viable strategy for cancer therapeutics.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

November 2013

Volume

4

Issue

11

Start / End Page

2144 / 2153

Location

United States

Related Subject Headings

  • Transfection
  • Neoplasms
  • Neoplasm Proteins
  • Methylation
  • Humans
  • Histones
  • Histone Demethylases
  • Histone Acetyltransferases
  • DNA-Binding Proteins
  • Cell Movement
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Guo, C., Chen, L. H., Huang, Y., Chang, C.-C., Wang, P., Pirozzi, C. J., … He, Y. (2013). KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation. Oncotarget, 4(11), 2144–2153. https://doi.org/10.18632/oncotarget.1555
Guo, Changcun, Lee H. Chen, Yafen Huang, Chun-Chi Chang, Ping Wang, Christopher J. Pirozzi, Xiaoxia Qin, et al. “KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation.Oncotarget 4, no. 11 (November 2013): 2144–53. https://doi.org/10.18632/oncotarget.1555.
Guo C, Chen LH, Huang Y, Chang C-C, Wang P, Pirozzi CJ, et al. KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation. Oncotarget. 2013 Nov;4(11):2144–53.
Guo, Changcun, et al. “KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation.Oncotarget, vol. 4, no. 11, Nov. 2013, pp. 2144–53. Pubmed, doi:10.18632/oncotarget.1555.
Guo C, Chen LH, Huang Y, Chang C-C, Wang P, Pirozzi CJ, Qin X, Bao X, Greer PK, McLendon RE, Yan H, Keir ST, Bigner DD, He Y. KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation. Oncotarget. 2013 Nov;4(11):2144–2153.

Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

November 2013

Volume

4

Issue

11

Start / End Page

2144 / 2153

Location

United States

Related Subject Headings

  • Transfection
  • Neoplasms
  • Neoplasm Proteins
  • Methylation
  • Humans
  • Histones
  • Histone Demethylases
  • Histone Acetyltransferases
  • DNA-Binding Proteins
  • Cell Movement