RUNX3 is oncogenic in natural killer/T-cell lymphoma and is transcriptionally regulated by MYC

Abstract

RUNX3, runt-domain transcription factor, is a master regulator of gene expression in major developmental pathways. It acts as a tumor suppressor in many cancers but is oncogenic in certain tumors. We observed upregulation of RUNX3 mRNA and protein expression in nasal-type extranodal natural killer (NK)/T-cell lymphoma (NKTL) patient samples and NKTL cell lines compared to normal NK cells. RUNX3 silenced NKTL cells showed increased apoptosis and reduced cell proliferation. Potential binding sites for MYC were identified in the RUNX3 enhancer region. Chromatin immunoprecipitation–quantitative PCR revealed binding activity between MYC and RUNX3. Co-transfection of the MYC expression vector with RUNX3 enhancer reporter plasmid resulted in activation of RUNX3 enhancer indicating that MYC positively regulates RUNX3 transcription in NKTL cell lines. Treatment with a small-molecule MYC inhibitor (JQ1) caused significant downregulation of MYC and RUNX3, leading to apoptosis in NKTL cells. The growth inhibition resulting from depletion of MYC by JQ1 was rescued by ectopic MYC expression. In summary, our study identified RUNX3 overexpression in NKTL with functional oncogenic properties. We further delineate that MYC may be an important upstream driver of RUNX3 upregulation and since MYC is upregulated in NKTL, further study on the employment of MYC inhibition as a therapeutic strategy is warranted.

Integrated genomic analysis identifies deregulated JAK/STAT-MYC-biosynthesis axis in aggressive NK-cell leukemia

“…Our findings suggest that targeted therapies against IL10, JAK-STAT signaling, MYC or nucleotide synthesis/glycolysis hold great promise for ANKL, and thus, future investigations of these pathways are warranted ( Figures 5C and 6). Recently, therapeutic utility of MYC inhibition has been revealed in NK-cell neoplasms, suggesting that MYC activation may represent a common mechanism in the pathogenesis of ANKL and NKTCL [47]. The hypothesis that nucleotide synthesis should be exploited for treatment is also supported by current clinical evidence.…”

Advances in multiple omics of natural-killer/T cell lymphoma

“…In according with CNV findings, downregulation of tumor suppressor genes in 6q21 ( PRDM1 , ATG5 , AIM1 ) are confirmed by microarray analysis [ 27 , 32 ]. As for individual genes, it is noteworthy that MYC induces upregulation of EZH2 and RUNX3 , both of which exert cascade effect of transcriptional activation during lymphomagenesis [ 36 , 37 ]. Using RNA sequencing technology, overexpression of KIR2DL4 is reported in malignant NK cells [ 38 ].…”

The Genomics and Molecular Biology of Natural Killer/T-Cell Lymphoma: Opportunities for Translation

“…Runt-domain transcription factor 3 (RUNX3), a master transcriptional regulator in major developmental pathways, is another gene that is positively regulated by C-MYC [ 38 ]. RUNX3 can function as either a tumor suppressor or oncogene, depending on tumor type [ 39 ].…”

“…In cytotoxic T and NK cells, it has been shown to mediate transcriptional activation of genes involved in lymphocyte activation, proliferation, and effector function, which include interferon gamma (IFN-gamma) perforin and granzyme B [ 40 ]. RUNX3 expression is upregulated in ENKTL, as well as in the majority of high-grade B-cell lymphomas and peripheral T-cell lymphomas [ 38 ]. SiRNA -induced silencing of RUNX3 resulted in increased apoptosis and reduced cell proliferation in ENKTL cell lines, suggesting an oncogenic role for RUNX3 in ENKTL.…”

“…SiRNA -induced silencing of RUNX3 resulted in increased apoptosis and reduced cell proliferation in ENKTL cell lines, suggesting an oncogenic role for RUNX3 in ENKTL. Inhibition of MYC by a novel small molecule inhibitor, JQ1, resulted in downregulation of RUNX3 transcripts [ 38 ]. The precise mechanism of RUNX3-mediated reduction in cellular proliferation and increased apoptosis remains to be further delineated.…”