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An Enhancer-specific Epigenetic Switch Underlies the Tumor-specific Function of the MYC Oncogene

By Stuart P. Atkinson, Ph.D.

December 18, 2025

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Enhancer “Invasion” by MYC as a Cancer-specific Regulatory Mechanism?

The commonly observed overexpression of the oncogenic transcription factor MYC drives multiple hallmarks of cancer progression (e.g., proliferation, metabolism, and invasion) (Meškytė et al.), in part by binding to active promoters to induce pro-tumorigenic transcriptomic profiles. While many view MYC binding to promoters as a ubiquitous cancer-associated phenomenon, studies highlighting the cancer-type-specific manner in which MYC influences tumorigenesis (Ji et al., Qiu et al., and Zeid et al.) have raised some thorny questions regarding this view.

A seemingly secondary role for MYC involves the “invasion” of distal enhancers (Zeid et al., Lin et al., Walz et al., See et al., and Sabò et al.), although related studies have suggested that this mechanism arises from “spillover” from saturated MYC binding at promoters and suffers from a general lack of gene-regulatory potential (Walz et al. and Nie et al.).

In an effort to describe the functional significance of MYC binding at enhancer elements, a new study from the laboratory of Rasmus Siersbæk (University of Southern Denmark) now reports that MYC regulates enhancer activity to promote cancer type-specific gene programs, which hold prognostic power. Their new Nature Genetics paper provides evidence that MYC cooperates with additional transcription factors to drive the expression of cancer type-specific gene programs through the induction of an enhancer-specific epigenetic switch and proposes bromodomain and extraterminal domain (BET) and GCN5 inhibition as a potent anti-cancer therapeutic strategy (Jakobsen et al.).

Can this study of MYC binding at enhancer elements in cancer cells provide promising epigenetic targets in the battle against tumorigenesis?

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Does an Enhancer-Specific Epigenetic Switch Represent a New Therapeutic Target for MYC-Driven Tumorigenesis?

Initial ChIP-seq experiments in breast cancer cell lines with intermediate levels of MYC overexpression demonstrated that 70-80% of MYC binding sites lay within promoter-distal regions and overlapped with known enhancer regions. Comparing MYC binding across a diverse range of cancer cell lines revealed that this transcription factor commonly bound the same promoters; however, they also found that MYC bound clinically relevant enhancers in a cancer type-specific manner, thanks to cooperation between MYC and cancer type-specific transcription factors. In addition, analysis of transposase-accessible chromatin with sequencing (ATAC-seq) data revealed an overlap between open chromatin regions and MYC-bound enhancers in cancer cells. While MYC binding at promoters activated the same gene program across cancer types, this new study demonstrated that MYC binding to enhancers promoted distinct, cancer-type-specific prognostic gene expression programs, facilitated by the formation of chromatin loops between enhancers and nearby genes.

Quite why MYC plays different functional roles at enhancers and promoters remains unclear; however, the authors suggest that differences in chromatin-associated proteins between these regulatory regions (dictated by distinct DNA motif composition) may play a role (Andersson & Sandelin), which agrees with the “coalition model” that proposes the MYC interactome as a determinant of MYC function (Lourenco et al.).

While MYC regulates pause-release at target gene promoters (Rahl et al.) and a recent paper revealed that pause-release also plays an important role in enhancer transcription (Henriques et al.), the authors of this new study discovered that MYC recruited RNA polymerase II (RNAP II) to enhancers rather than promoting pause-release to induce the production of small non-coding RNAs termed enhancer RNAs (a hallmark of active enhancers) (Kim et al.). Furthermore, the team demonstrated that MYC induced an epigenetic switch at the H3K9 residue at target enhancer loci – increasing levels of the permissive H3K9ac modification and decreasing levels of the repressive H3K9me2/1 modification – thanks to the combined action of the H3K9 lysine demethylase 3A (KDM3A) and the H3K9 histone acetyltransferase GCN5. Additionally, they found that enhancer-specific recruitment of BET proteins such as BRD4 – which binds regions of highly acetylated histones - by MYC promoted enhancer activation to facilitate RNAPII recruitment.

The implication of BRD4 and GCN5 in this mechanism provides therapeutic opportunities targeting MYC enhancer function. While this study suggests that BET inhibitors directly block MYC activity at enhancers by inhibiting MYC-mediated BRD4 recruitment in addition to repressing MYC expression (Doroshow et al.), the observed global effect of the inhibitor on RNAPII recruitment indicated that current BET inhibitors do not selectively target MYC enhancer function. Fortunately, among other histone modifiers likely to co-regulate MYC enhancer function, the authors highlighted GCN5 inhibition as a more selective approach for targeting MYC function at enhancers, provided that more selective compounds can be developed (Haque et al.).

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An Epigenetic Model for Cancer-specific Oncogenic Functions of MYC

The findings of this exciting study suggest that cancer-specific enhancer activation by MYC binding involves a KDM3A- and GCN5-associated repressive-to-permissive epigenetic switch that recruits BET proteins such as BRD4 to facilitate RNAPII loading and induce enhancer RNA transcription. Furthermore, the authors propose a revised gene-specific affinity model based on these data (Lorenzin et al.); here, MYC target gene specificity does not rely on MYC binding to promoters and instead involves cooperativity with lineage-determining transcription factors at enhancers.

Of note, this research employed spike-in chromatin from Active Motif for ChIP-seq spike-in normalization, allowing for confident comparisons between ChIP-seq datasets.

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About the author

Stuart P. Atkinson, Ph.D.

Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!

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