Journal article
Increasing G9a automethylation sensitizes B acute lymphoblastic leukemia cells to glucocorticoid-induced death
Cell death & disease, Vol.9(10), pp.1038-13
10/10/2018
DOI: 10.1038/s41419-018-1110-z
PMCID: PMC6180122
PMID: 30305606
Abstract
Synthetic glucocorticoids (GCs) are used to treat lymphoid cancers, but many patients develop resistance to treatment, especially to GC. By identifying genes that influence sensitivity to GC-induced cell death, we found that histone methyltransferases G9a and G9a-like protein (GLP), two glucocorticoid receptor (GR) coactivators, are required for GC-induced cell death in acute lymphoblastic leukemia (B-ALL) cell line Nalm6. We previously established in a few selected genes that automethylated G9a and GLP recruit heterochromatin protein 1 gamma (HP1 gamma) as another required coactivator. Here, we used a genome-wide analysis to show that HP1 gamma is selectively required for GC-regulated expression of the great majority of GR target genes that require G9a and GLP. To further address the importance of G9a and GLP methylation in this process and in cell physiology, we found that JIB-04, a selective JmjC family lysine demethylase inhibitor, increased G9a methylation and thereby increased G9a binding to HP1 gamma. This led to increased expression of GR target genes regulated by G9a, GLP and HP1 gamma and enhanced Nalm6 cell death. Finally, the KDM4 lysine demethylase subfamily demethylates G9a in vitro, in contrast to other KDM enzymes tested. Thus, inhibiting G9a/GLP demethylation potentially represents a novel method to restore sensitivity of treatment-resistant B-ALL tumors to GC-induced cell death.
Details
- Title: Subtitle
- Increasing G9a automethylation sensitizes B acute lymphoblastic leukemia cells to glucocorticoid-induced death
- Creators
- Coralie Poulard - University of Southern CaliforniaEstelle Baulu - University of Southern CaliforniaBrian H. Lee - University of Southern CaliforniaMiles A. Pufall - HoldenMichael R. Stallcup - University of Southern California
- Resource Type
- Journal article
- Publication Details
- Cell death & disease, Vol.9(10), pp.1038-13
- DOI
- 10.1038/s41419-018-1110-z
- PMID
- 30305606
- PMCID
- PMC6180122
- NLM abbreviation
- Cell Death Dis
- ISSN
- 2041-4889
- eISSN
- 2041-4889
- Publisher
- Springer Nature
- Number of pages
- 13
- Grant note
- K99/R00CA149088 / NIH/NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) 01-224 / Roy J. Carver Chartiable Trust P30CA014089 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Molecular and Cell Biology Core Facilities P30CA014089 / National Institutes of Health Cancer Center Support; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01DK043093 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) American Cancer Society-IRG program R37DK055274; R01DK043093 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Holden Comprehensive Cancer Center
- Language
- English
- Date published
- 10/10/2018
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9984293087802771
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