Abstract
Aberrant DNA methylation is a hallmark of cancer. However, our understanding of how tumor cell-specific DNA methylation patterns are established and maintained is limited. Here, we report that in T-cell acute lymphoblastic leukemia (T-ALL) and Burkitt’s lymphoma the MYC oncogene causes overexpression of DNA methyltransferase (DNMT) 1 and 3B, which contributes to tumor maintenance. By utilizing a tetracycline-regulated MYC transgene in a mouse T-ALL (EμSRα-tTA;tet-o-MYC) and human Burkitt’s lymphoma (P493-6) model, we demonstrated that DNMT1 and DNMT3B expression depend on high MYC levels, and that their transcription decreased upon MYC-inactivation. Chromatin immunoprecipitation indicated that MYC binds to the DNMT1 and DNMT3B promoters, implicating a direct transcriptional regulation. Hence, shRNA-mediated knock-down of endogenous MYC in human T-ALL and Burkitt’s lymphoma cell lines downregulated DNMT3B expression. Knock-down and pharmacologic inhibition of DNMT3B in T-ALL reduced cell proliferation associated with genome-wide changes in DNA methylation, indicating a tumor promoter function during tumor maintenance. We provide novel evidence that MYC directly deregulates the expression of both de novo and maintenance DNMTs, showing that MYC controls DNA methylation in a genome-wide fashion. Our finding that a coordinated interplay between the components of the DNA methylating machinery contributes to MYC-driven tumor maintenance highlights the potential of specific DNMTs for targeted therapies.
Highlights
C-MYC encodes for a transcription factor that is a key regulator of a wide variety of cellular processes
By utilizing a tetracycline-regulated MYC transgene in a mouse T-cell acute lymphoblastic leukemia (T-ALL) (EμSRα-tTA;tet-oMYC) and human Burkitt’s lymphoma (P493-6) model, we demonstrated that DNMT1 and DNMT3B expression depend on high MYC levels, and that their transcription decreased upon MYC-inactivation
We found DNMT1 and DNMT3B to be consistently overexpressed in transgenic models, human tumor cell lines, as well as in clinical specimens
Summary
C-MYC (here referred to as MYC) encodes for a transcription factor that is a key regulator of a wide variety of cellular processes (reviewed in [1]). MYC is well known as a site-specific transcription factor regulating the expression of hundreds of target genes. There is growing evidence that MYC induces genome-wide changes in the epigenetic landscape of the cell as an important part of its neoplastic features, including alterations of post-translational histone modifications (reviewed in [12]). We reported that the inactivation of MYC in T-ALL causes changes in global histone H4 acetylation, H3K9me and H3K4me associated with cellular senescence and tumor regression [15] These results suggest that in tumors that elicit oncogene addiction, the MYC oncogene establishes and maintains a genomewide epigenetic state, while MYC inactivation triggers dramatic alterations in chromatin structure leading to cellular senescence as an important mechanism of tumor regression. Tumor cells typically display global hypomethylation of repetitive DNA elements, which contributes to genomic instability, while promoter and CpG island hypermethylation extinguishes transcription of tumor suppressor genes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
