Decitabine represses translocated MYC oncogene in Burkitt lymphoma

Abstract

Burkitt lymphoma (BL) is caused by translocation of the MYC gene to an immunoglobulin locus resulting in its constitutive expression depending on the activity of the immunoglobulin (Ig) enhancer elements. Treatment of BL cell lines with epigenetic modifiers is known to repress B-cell-specific genes and to up-regulate B-cell-inappropriate genes including the transcription repressor ID2 expression. We found that the DNA methyltransferase inhibitor decitabine/5-aza-2-deoxycytidine (5-aza-dC) represses the MYC oncogene on RNA and protein levels by inducing ID2. Down-regulation of MYC was associated with repression of transcriptional activity of the Ig locus and with inhibition of proliferation. The induction of ID2 can be in part explained by activation of the transcription factor NF-κB. We conclude that up-regulation of ID2 contributes to anti-tumour activity of 5-aza-dC via repression of Ig locus activity and consequently MYC expression.

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“…Immunoblot was done in RAW264.7 cells as described [10,15]. Primary antibodies which included mouse anti-β-Actin (1:500 dilution) were from BOSTER (Wuhan, China).…”

“…Secondary antibodies included goat anti-rabbit IgG-horseradish peroxidase (HRP; sc-2004, from Santa Cruz Biotechnology) and donkey anti-goat IgG-HRP (sc-2020; Santa Cruz Biotechnology). EMSA was performed as described before [10]. The DNA-binding activity of NF-κB and AP-1 was detected using a LightShift Chemiluminescent EMSA Kit (Thermo Fisher Scientific, China).…”

“…Quantitative real-time polymerase chain reaction (qRT-PCR) was done as described [10,15]. Briefly, total RNA was prepared from RAW264.7 cells using TRIzol reagents (Invitrogen), first-strand cDNA was synthesized with MMLV reverse transcriptase (Promega, Madison, WI).…”

“…Demethylating reagents including decitabine could release the repression, leading to perturbed transcription program. Recently we and others showed that, in B cell lymphomas, decitabine repressed B cell specific gene transcription at least partly by upregulation of B lineage-inappropriate genes [10,11]. In B cell lymphomas especially Burkitt lymphomas and Follicular lymphomas, decitabine suppressed the transcription program supporting the expression of translocated oncogenes MYC and BCL-2, leading to impaired tumor cell fitness.…”

“…In B cell lymphomas especially Burkitt lymphomas and Follicular lymphomas, decitabine suppressed the transcription program supporting the expression of translocated oncogenes MYC and BCL-2, leading to impaired tumor cell fitness. In Burkitt lymphomas characterized by absence of NF-κB signaling [12], decitabine activated NF-κB, which contributes to its tumor suppressing effects [10].…”