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Epigenetic Changes Can Prompt Tumorigenesis, Even in the Absence of Driver Mutations

No Mutations!

By Stuart P. Atkinson, Ph.D.

June 12, 2024

Introduction: Do Non-Genetic Mechanisms Suffice to Initiate Tumorigenesis?

While the accumulation of somatic mutations can prompt cancer initiation and support disease progression, the epigenetic alterations known to underlie aspects of tumorigenesis (Timp and Feinberg, Marine et al., and Flavahan et al.) suggest the existence of additional drivers of malignant transformation. Low numbers of mutations encountered in certain cancer types had additionally suggested that epigenetic alterations could drive tumorigenesis; however, whether epigenetic mechanisms sufficed to initiate tumorigenesis in the absence of driver mutations remained unknown (Chatterjee et al. and Feinberg, 2018). That was until the publication of an absorbing study into transient epigenetic dysregulation in fruit flies by researchers guided by Anne-Marie Martinez and Giacomo Cavalli at the University of Montpellier (Parreno et al., 2024).

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Transient Loss of Polycomb-mediated Transcriptional Silencing in Fruit Flies: A View to a Potential Mechanism?

Parreno et al. focused on polycomb group proteins in the fruit fly Drosophila, given their conservation between flies and humans and their well-understood roles in normal development (Chan and Morey), cell fate alterations (Parreno et al., 2022), and cancer (Schuettengruber et al.). They transiently perturbed polycomb group protein-mediated transcriptional silencing during early fly development by depleting polycomb repressive complex 1 subunits through a thermosensitive RNA interference system. Fascinatingly, this short-term epigenetic dysregulation sufficed to trigger irreversible neoplastic transformation in the absence of recurrent driver mutations; as such, the authors defined the tumors that subsequently formed as epigenetically initiated cancers.

Further analysis revealed that this loss of transcriptional silencing activity prompted the irreversible derepression of tumorigenesis-associated genes, which included critical members of the JAK-STAT signaling pathway that sustain cell growth, proliferation, loss of cell polarity, cell migration, and cytokine activity (Classen et al.). Of note, polycomb perturbation-induced tumorigenesis required the aberrant activation of a JAK-STAT target gene zfh1 (the fly homolog of the ZEB1 oncogene), which functions to block cell differentiation.

Active Motif CUT&Tag R-loop Kit

CUT&RUN analysis revealed that transient loss of polycomb proteins modulated the chromatin state of target genes, which associated with the altered transcriptomic profile observed; however, they observed irreversible tumorigenesis-associated transcriptional alterations even after the reestablishment of a normal chromatin landscape, which may derive from the irreversible increases in chromatin accessibility (as assessed by ATAC-seq) caused by the binding of specific transcription factors that can prompt the inheritance of altered cell fates.

Overall, the authors describe a complex cascade of events - triggered by epigenetic dysregulation brought about by the transient loss of polycomb proteins - that represent a self-sustaining tumorigenic mechanism that functions in the absence of driver mutations and even in the subsequent presence of normalized polycomb group protein levels.

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Evidence for Epigenetically Initiated Cancers in Human Patients?

Fascinatingly, the authors finally reported a survey of human multiple myeloma patient data, which indicated an association between the low-level expression of canonical PRC1 subunit genes and poorer patient prognosis, consistent with a suppressive role for PRC1 in human tumor types. Future studies addressing epigenetic dysregulation's role in these tumors may provide greater insight and underscore the importance of this newly discovered mechanism.

For more on how epigenetic dysregulation can prompt tumorigenesis in the absence of driver mutations, see Nature, April 204.

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About the author

Stuart P. Atkinson

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!

Contact Stuart on Twitter with any questions

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