Cancer-associated DNA hypomethylation is as prevalent as cancer-linked hypermethylation, but these two types of epigenetic abnormalities usually seem to affect different DNA sequences. Much more of the genome is generally subject to undermethylation rather than overmethylation. Genomic hypermethylation in cancer has been observed most often in CpG islands in gene regions. In contrast, very frequent hypomethylation is seen in both highly and moderately repeated DNA sequences in cancer, including heterochromatic DNA repeats, dispersed retrotransposons, and endogenous retroviral elements. Also, unique sequences, including transcription control sequences, are often subject to cancer-associated undermethylation. The high frequency of cancer-linked DNA hypomethylation, the nature of the affected sequences, and the absence of associations with DNA hypermethylation are consistent with an independent role for DNA undermethylation in cancer formation or tumor progression. Increased karyotypic instability and activation of tumor-promoting genes by cis or trans effects, that might include altered heterochromatin-euchromatin interactions, may be important consequences of DNA hypomethylation which favor oncogenesis. The relationship of DNA hypomethylation to tumorigenesis is important to be considered in the light of cancer therapies involving decreasing DNA methylation. Inducing DNA hypomethylation may have short-term anticancer effects, but might also help speed tumor progression from cancer cells surviving the DNA demethylation chemotherapy.

DNA methylation in cancer: too much, but also too little.

Epigenetics is one of the most promising and expanding fields in the current biomedical research landscape. Since the inception of epigenetics in the 1940s, the discoveries regarding its implications in normal and disease biology have not stopped, compiling a vast amount of knowledge in the past decade. The field has moved from just one recognized marker, DNA methylation, to a variety of others, including a wide spectrum of histone modifications. From the methodological standpoint, the successful initial single gene candidate approaches have been complemented by the current comprehensive epigenomic approaches that allow the interrogation of genomes to search for translational applications in an unbiased manner. Most important, the discovery of mutations in the epigenetic machinery and the approval of the first epigenetic drugs for the treatment of subtypes of leukemias and lymphomas has been an eye-opener for many biomedical scientists and clinicians. Herein, we will summarize the progress in the field of cancer epigenetics research that has reached mainstream oncology in the development of new biomarkers of the disease and new pharmacological strategies.

Cancer epigenetics reaches mainstream oncology

Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia

Objective

To investigate whether the abnormal expression of matrix metalloproteinases (MMPs) 3, 9, and 13 and ADAMTS-4 by human osteoarthritic (OA) chondrocytes is associated with epigenetic “unsilencing.”



Methods

Cartilage was obtained from the femoral heads of 16 patients with OA and 10 control patients with femoral neck fracture. Chondrocytes with abnormal enzyme expression were immunolocalized. DNA was extracted, and the methylation status of the promoter regions of MMPs 3, 9, and 13 and ADAMTS-4 was analyzed with methylation-sensitive restriction enzymes, followed by polymerase chain reaction amplification.



Results

Very few chondrocytes from control cartilage expressed the degrading enzymes, whereas all clonal chondrocytes from late-stage OA cartilage were immunopositive. The overall percentage of nonmethylated sites was increased in OA patients (48.6%) compared with controls (20.1%): 20% versus 4% for MMP-13, 81% versus 47% for MMP-9, 57% versus 30% for MMP-3, and 48% versus 0% for ADAMTS-4. Not all CpG sites were equally susceptible to loss of methylation. Some sites were uniformly methylated, whereas in others, methylation was generally absent. For each enzyme, there was 1 specific CpG site where the demethylation in OA patients was significantly higher than that in controls: at −110 for MMP-13, −36 for MMP-9, −635 for MMP-3, and −753 for ADAMTS-4.



Conclusion

This study provides the first evidence that altered synthesis of cartilage-degrading enzymes by late-stage OA chondrocytes may have resulted from epigenetic changes in the methylation status of CpG sites in the promoter regions of these enzymes. These changes, which are clonally transmitted to daughter cells, may contribute to the development of OA.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.21300

Association between the abnormal expression of matrix-degrading enzymes by human osteoarthritic chondrocytes and demethylation of specific CpG sites in the promoter regions.

Apoptosis and senescence are cellular failsafe programmes that counteract excessive mitogenic signalling from activated oncogenes. Cancellation of apoptosis or senescence is therefore a prerequisite for tumour formation, and the ability of the cancer cell to disrupt these processes can be considered its 'lifeline'. Ironically, the efficacy of anticancer agents also depends on the activation of apoptosis or an acutely inducible form of cellular senescence. Understanding how the 'lifelines' of the cancer cell interfere with treatment sensitivity is of crucial importance for developing safer and more effective treatment strategies.

Senescence, apoptosis and therapy — cutting the lifelines of cancer

The genes at the INK4A/ARF locus at 9p21 are frequently involved in human cancer. Virtually all p16(INK4A) exon 2 (henceforth called p16) inactivation in pediatric acute lymphoblastic leukemia (ALL) occurs by gene deletion. The results of this study illustrate that real-time quantitative polymerase chain reaction is capable of detecting gene deletion in primary patient specimens with a precision not previously achieved by conventional methods. Importantly, this assay includes the detection of hemizygous deletions. The study revealed, strikingly, that the risk ratio for relapse for hemizygous deletion compared with no deletion was 6.558 (P =.00687) and for homozygous deletion was 11.558 (P =.000539). These results confirm and extend the authors' previous findings that homozygous deletion of p16 in pediatric ALL patients is an independent prognostic indicator of outcome from therapy.

Hemizygous p16(INK4A) deletion in pediatric acute lymphoblastic leukemia predicts independent risk of relapse.

Despite considerable work on the epigenetic control of tumor suppressor genes, little is known about the potential role of promoter CpG demethylation in the activation of oncogenes in lymphoid tumors. The HOX11 proto-oncogene is frequently activated in T-cell acute lymphoblastic leukemia (T-ALL). HOX11 activation can occur in the absence of translocation of the gene to the T-cell receptor locus (Salvati et al., 1995), implying that activation mechanisms must be involved other than the juxtaposition of the gene to adjacent enhancing sequences. We tested whether the methylation status of the proximal promoter was correlated with expression status in T-ALL and found that, in all cases, expression of HOX11 in T-ALL was associated with extensive demethylation of the proximal HOX11 promoter, regardless of whether or not translocation was involved. In contrast, cells that did not express HOX11 showed a more methylated pattern of CpG residues in the proximal promoter. Methylation of this sequence in vitro was sufficient to silence the proximal promoter. We propose a model in which the selection of leukemia clones via a pathway involving HOX11 expression requires the demethylation of its promoter as a prerequisite for additional gene activation mechanisms. © 2000 Wiley-Liss, Inc.

Promoter demethylation accompanies reactivation of the HOX11 proto-oncogene in leukemia.

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Hemizygous p16(INK4A) deletion in pediatric acute lymphoblastic leukemia predicts independent risk of relapse.

Promoter demethylation accompanies reactivation of the HOX11 proto-oncogene in leukemia.