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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 1γ (HP1γ) as another required coactivator. Here, we used a genome-wide analysis to show that HP1γ 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 HP1γ. This led to increased expression of GR target genes regulated by G9a, GLP and HP1γ 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.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood, representing 30% of all childhood cancers and 80% of childhood leukemias
Starting with a genome-wide short hairpin RNA screen, we recently demonstrated that coregulators G9a (EHMT2) and G9a-like protein (GLP; EHMT1) are required for efficient GC-induced apoptosis of the Nalm[6] B-ALL cell line[15]
heterochromatin protein 1γ (HP1γ) is required for G9a/GLP coactivator function Because we previously found that HP1γ is selectively required for GC-induced expression of several genes that require G9a and GLP as coactivators[13], we employed RNA interference and RNA-sequencing to explore whether this association applies genome-wide
Summary
Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood, representing 30% of all childhood cancers and 80% of childhood leukemias. Treatment consists of a combination of chemotherapeutic agents, including vincristine, L-asparaginase and synthetic glucocorticoid (GC) agonists, such as dexamethasone (dex) and prednisolone[1]. About 10–20% of children with ALL do not respond to combination chemotherapy that includes GC, or they develop resistance upon relapse; this treatment resistance is strongly correlated with GC insensitivity[2,3,4]. Adverse side effects, including osteoporosis, hyperglycemia, hyperlipidemia, insulin resistance, muscle wasting and obesity, are frequently associated with long-term, high-dose GC treatments, such that an increased number of patients experience life-threatening morbidity by their 30s, including heart and lung disease, secondary cancers and developmental problems[5,6]. Novel treatments based on an enhanced understanding of GC-induced cell death and mechanisms of resistance are clearly needed
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