Writing your first grant proposal? Optimizing that tricky Western blot? Programming an old PCR machine? Only a few things are more complex than our current understanding of the epigenetic links between aging and tumorigenesis, but this has not stopped a few valiant labs from doubling down and busting a few paradigms while they are at it!
In general, aging is the most important risk factor for cancer development; the older you are, the more likely you are to suffer from this often-devastating disease. But why? One hypothesis states that the accumulation of epigenetic alterations over time predisposes our cells to go rogue, but quite how they do it is open to interpretation. In a related hypothesis, the epigenetic profile of the senescent cells that accumulate in the aging body may foster tumorigenicity if cells can escape the senescent state. Furthermore, we also know that focal DNA hypermethylation and global DNA hypomethylation occur in both tumorigenesis and aging/senescence, suggesting an epigenetic link between the two processes.
Now, two studies from laboratories from opposite sides of the Atlantic have cut through some of the epigenetic complexity surrounding the link between aging and tumorigenesis to provide fresh insight into this highly complicated relationship.
Same Old DNA Hypomethylation, Different Chromatin Context!
Our first study from the labs of Agustín F. Fernández and Mario F. Fraga (Universidad de Oviedo, Spain) aimed to fill a few knowledge gaps concerning DNA hypomethylation during aging and tumorigenesis. Previous studies have discerned a robust link between the chromatin patterns of DNA hypermethylation sites in tumorigenesis and aging, although few have reported on the chromatin context of DNA hypomethylation. This prompted the authors to integrate 450K array data generated by The Cancer Genome Atlas consortium from 2,311 healthy and tumoral samples obtained from differentially aged individuals with histone, chromatin state, and transcription factor binding site data from the NIH Roadmap Epigenomics and ENCODE projects.
After the computational processing winded down and the dust settled, Pérez and colleagues discovered:
- Hyper- and hypo-methylated changes display a similar distribution throughout the genome but also exhibit some tissue-independent alterations
- Bidirectional changes in DNA methylation occur during tumorigenesis, while hypermethylation predominates during aging
- Interestingly, the authors identified common DNA methylation signature that occurred across all tumors, and, separately, a common DNA methylation signature in many aged tissues
- Most tumor types do not exhibit age-associated DNA methylation changes, which is in agreement with the reprogramming of the epigenetic clock in cancer cells
- As expected, hypermethylated regions associate with both aging and tumorigenesis display chromatin modifications characteristic of bivalent chromatin domains
- Hypermethylation changes tend to occur in CpG-dense regions, associated with binding of the EZH2 and SUZ12 polycomb components, and affect developmentally-associated genes
- However, hypomethylated DNA sequences associate with different chromatin contexts during aging and tumorigenesis
- During aging, DNA hypomethylated sequences occur at enhancers with the activating H3K4me1 modification
- During tumorigenesis, DNA hypomethylation arises at heterochromatic sites displaying the repressive H3K9me3 modification
- While hypomethylated regions in tumorigenesis affect genes associated with cellular signaling, the study observed no strong correlations for aging
What does this all mean? The data gathered here suggests that while the story may appear straightforward for DNA hypermethylation, DNA hypomethylation occurs in different chromatin contexts during tumorigenesis and aging, suggesting that different mechanisms may be at play.
DNA Methylation Profiling: Busting Cancer Paradigms and Tracking Cancer Risks
Our second study from the labs of Stephen B. Baylin and Hariharan Easwaran (Johns Hopkins University, Baltimore, USA) employed DNA methylation profiling to investigate the hypotheses that tumor-promoting epigenetic states arise in the senescent cells that accumulate in the aging body. Xie and colleagues compared DNA methylation alterations during the tumorigenic transformation of engineered fibroblasts and replicative senescence of unmodified fibroblasts with the 450K array.
Their new work not only busts a cancer paradigm, but may also provide a new means to stratify cancer patients into risk categories:
- While DNA methylation patterns during tumorigenesis and senescence appear globally similar, transformation induces a significantly different DNA methylation state when compared to senescence
- Senescence-associated promoter hypermethylation events mainly involve the silencing of biosynthesis- and metabolism-associated genes in cells unlikely to undergo transformation
- The shutdown of biosynthetic processes via DNA methylation likely inhibits tumor development, thereby representing an epigenetic contribution to the Hayflick phenomenon
- Methylation changes during transformation arise stochastically at pro-survival and developmental gene promoters and occur independently of senescence-associated changes
- Many of these genes display promoter hypermethylation in primary tumors
- Of note, the study discovered a subset of self-renewal and cell survival genes commonly methylated during tumorigenic transformation and senescence
- These genes represent hotspots for DNA hypermethylation in primary tumors and aging tissues and, perhaps, a crucial means to track cancer risk
Overall, these new findings do not support a role for senescence-associated methylation in tumorigenesis but do support a role for the random DNA hypermethylation events that accumulate during normal aging; specifically, patients who accrue DNA methylation at select gene promoters may present with an increased likelihood of tumorigenesis.
Conclusions: Complexity Cut?
As with many good studies, cutting through the epigenetic complexities has redefined some of our basic assumptions regarding the links between aging and cancer and provided further engaging questions moving forward. Future research may uncover the different mechanisms controlling DNA hypomethylation in during aging/tumorigenesis and refine the use of DNA methylation analysis as a potent means to define cancer risk.
For more on the complexities of DNA hypomethylation events during tumorigenesis and aging, see Aging Cell, March 2018, and for the low down on DNA methylation and cancer risk, head on over to Cancer Cell, February 2018.