Hijacking a key chromatin modulator creates epigenetic vulnerability for MYC-driven cancer

Abstract

While the genomic binding of MYC protein correlates with active epigenetic marks on chromatin, it remains largely unclear how major epigenetic mechanisms functionally impact the tumorigenic potential of MYC. Here, we show that, compared with the catalytic subunits, the core subunits, including DPY30, of the major H3K4 methyltransferase complexes were frequently amplified in human cancers and selectively upregulated in Burkitt lymphoma. We show that DPY30 promoted the expression of endogenous MYC and was also functionally important for efficient binding of MYC to its genomic targets by regulating chromatin accessibility. Dpy30 heterozygosity did not affect normal animal physiology including lifespan, but significantly suppressed Myc-driven lymphomagenesis, as cells failed to combat oncogene-triggered apoptosis as a result of insufficient epigenetic modulation and expression of a subset of antiapoptotic genes. Dpy30 reduction also greatly impeded MYC-dependent cellular transformation, without affecting normal cell growth. These results suggest that MYC hijacks a major epigenetic pathway - H3K4 methylation - to facilitate its molecular activity in target binding and to coordinate its oncogenic program for efficient tumorigenesis, meanwhile creating "epigenetic vulnerability." DPY30 and the H3K4 methylation pathway are thus potential epigenetic targets for treating certain MYC-driven cancers.

MYC in Germinal Center‐derived lymphomas: Mechanisms and therapeutic opportunities

“…Sequence‐specific transcription factors (TFs) contribute to the recruitment of co‐activators and/or components of the basal transcription machinery to their cognate binding elements in the genome: this is a reciprocal relationship, however, as many TFs depend on the same interactions to access target regulatory regions in the genome, prior to sequence‐specific DNA binding . MYC, in particular, requires an active, open chromatin conformation to access its target DNA sequences, which is facilitated by its interaction with proteins such as WDR5, DPY30 (two components of the H3K4 methyltransferase complex SET1/MLL), BPTF (a component of the NURF chromatin remodeling complex) and possibly others among numerous interacting co‐factors . This initial step in genome recognition might be susceptible to pharmacological intervention, as exemplified by targeting of the MYCN‐WDR5 interaction in neuroblastoma cells, with a consequent reduction in MYCN‐dependent transcription and cell growth .…”

“…This initial step in genome recognition might be susceptible to pharmacological intervention, as exemplified by targeting of the MYCN‐WDR5 interaction in neuroblastoma cells, with a consequent reduction in MYCN‐dependent transcription and cell growth . DPY30 might also be promising target in this regard, as its gene was frequently amplified in human cancer, was upregulated in BL, and was limiting for lymphomagenesis in Eμ‐ myc mice …”

Specific inhibition of DPY30 activity by ASH2L-derived peptides suppresses blood cancer cell growth

“…We have shown that DPY30 depletion impaired c-MYC (MYC) expression and growth of several MLL-rearranged leukemias without affecting K562 leukemia cells driven by different mechanisms (17). We have also found that the expression of the core subunits including DPY30 was significantly upregulated in primary MYCtranslocated Burkitt's lymphoma samples comparing to other lymphoma subtypes (20). Deleting one Dpy30 allele in mice significantly delayed the Eµ-MYC-driven lymphomagenesis, with virtually no effect on normal mouse physiology.…”

“…An important role of DPY30 in tumorigenesis is also increasingly evident. Genes encoding the SET1/MLL complex core subunits including DPY30 are frequently amplified across a wide variety of human cancers (20). DPY30 is overexpressed in gastric cancer cells and also positively regulates the proliferation and motility of these cells (21).…”

“…Moreover, we also show that Dpy30 heterozygosity confers primary mouse embryonic fibroblast cells remarkable resistance to oncogenic transformation without affecting their normal growth. Molecular dissections show that, in addition to regulating expression of endogenous MYC, DPY30 is important for MYC's activity as a transcription factor to bind to its genomic targets, thus providing two different levels of MYC regulation (20). These results have established DPY30 as a critical regulator for MYC-dependent lymphomagenesis and leukemogenesis, and may represent a potential target for treating these hematopoietic malignancies.…”