An Epigenetic Exploration of Cancer

The search to understand and treat cancer triggers a desire to look for the cause. For decades, many clinicians and scientists suggested that genes cause cancer. Siddhartha Mukherjee wrote in The Emperor of All Maladies: A Biography of Cancer, “Cancer, we have discovered, is stitched into our genome.” Indeed, cancer surely arises from a person’s genes when the disease is inherited, but that only accounts for about one cancer in ten.¹ In other cases, gene mutations that accumulate over a lifetime can also set off cancer. Nonetheless, many scientists now search for a more elusive, far-more-than-one-word answer to the cause of cancer, and it’s epigenetics.

According to the U.S. Centers for Disease Control and Prevention (CDC), “Epigenetics is the study of how your behaviors and environment can cause changes that affect the way your genes work. Unlike genetic changes, epigenetic changes are reversible and do not change your DNA sequence, but they can change how your body reads a DNA sequence.”² Epigenetic changes include a range of processes, such as DNA methylation and modifications to histones. Those changes can cause cancer.

“Abnormal epigenetic activity has been implicated in the development and progression of numerous cancers,” says proteomics expert Danette Daniels, PhD, of Foghorn Therapeutics in Cambridge, MA.

In general, research reveals that the causes of cancer go beyond a genetic sequence. From the Josep Carreras Leukaemia Research Institute in Barcelona, Spain, associate scientist Veronica Davalos, PhD, and director Manel Esteller, MD, PhD, wrote: “Cancer development is driven by the accumulation of alterations affecting the structure and function of the genome.”³

That accumulation of alterations can arise from many mechanisms, and epigenetics alone creates a broad landscape to explore. In fact, the epigenetics of cancer is so complex that it takes teams of researchers to unravel. “What’s been so exciting to me is that the field has expanded so much that no one scientist or group of scientists can keep up with the whole thing outside their microcosm,” says oncologist Stephen Baylin, MD, of Johns Hopkins University School of Medicine in Baltimore, MD. “The good thing about that is it’s building an understanding and a need for synthesis that’s going to benefit the entire field.”

As a result, scientists and clinicians keep making headway on the connection between epigenetics and cancer.

The significance of structure

“Inside every cell is approximately two meters of DNA that is wound around histone proteins and packaged into chromatin, providing an efficient way to organize DNA in the nucleus,” explains Susan Clark, PhD, head of the epigenetics research laboratory at the Garvan Institute of Medical Research and conjoint professor at UNSW Medicine & Health in Australia. “However, we now understand that this 3D chromatin architecture is different in each cell type and determines which segments of the DNA are accessible or inaccessible to the cellular machinery required for gene expression.”

Epigenetics can change this 3D chromatin architecture. As Clark points out, “epigenetic protein complexes known as ‘writers’ can add chemical modifications to histones to promote chromatin remodeling, which switches genes on, and ‘erasers’ remove these marks and switch genes off.” In addition, a writer can add a repressive modification that turns off genes. These mechanisms control gene expression, usually to the benefit of a person. “However, when these mechanisms malfunction, they can change the way a cell behaves, which can lead to cancer,” Clark says.

Proteins can also directly modify the DNA through processes such as methylation. As Baylin points out, DNA methylation caught the attention of cancer scientists decades ago. As he adds, “We still think it’s critically important.” As an example, Daniela Matei, MD, chief of reproductive science in medicine in the department of obstetrics and gynecology at the Northwestern University Feinberg School of Medicine in Chicago, IL, and her colleagues showed clinical benefits of inhibiting methylation in patients with ovarian cancer.⁴

In fact, this was not new territory for Baylin. “For a number of years, we’ve addressed the changes that we have seen that are cancer specific, where DNA methylation is either lost or gained that really shouldn’t be there,” he says.

Baylin’s team coined the term viral mimicry in a paper⁵ published in 2015 with Katherine Chiappinelli, PhD, of the George Washington University School of Medicine & Health Sciences in Washington, DC, alongside another⁶ from Daniel de Carvalho, PhD, who was then working in the lab of Peter Jones, PhD, at the University of Toronto and now scientific co-founder and chief scientific officer of Adela. “When you block DNA methylation by drug treatment, or in combination with drugs targeting a certain accompanying repressive chromatin state⁷, a cell that encounters a cancer cell says: ‘I just saw a virus so I’m going to respond by defending against that,’” Baylin explains. In that way, a person’s immune system might be turned against the cancer.

Beyond epigenetic changes to DNA, modifications to RNA can also play a role in cancer. As Esteller and his colleagues wrote in a 2023 review: “Chemical modifications of RNA molecules—the so-called epitranscriptome—have been found to regulate various aspects of RNA function and homeostasis.”⁸ Changes in RNA can influence the proteins produced, and thereby participate in cancer. As Esteller summarizes this: Epigenetic aberrations can “alter the chemical modifications of RNA—epitranscriptomic changes—causing profound changes in the natural history of many tumor types.”

Multiple approaches to treatment

Although the intricacies of the pathways that activate cancer intrigue scientists, a person with one of these diseases seeks the answer to only one question: How can it be treated? Epigenetics promises new answers and options for patients.

“Early epigenetic inhibitors to key chromatin regulators were developed to treat disease,” Daniels says. “However, many of these inhibitors had broad activity and were not highly selective.” One of the early goals of Foghorn, she says, was to “regulate activity at specific genomic locations with much more nuance and specificity.”

Scientists at Foghorn, though, looked beyond inhibition as a method of treating cancer. “We also have expanded to different modalities with protein disruptors and targeted protein degraders,” Daniels says. “This has enabled targeting non-enzymatic disease drivers of larger epigenetic complexes working at inappropriate DNA locations.”

For example, Foghorn scientists looked at chromatin and one of its key epigenetic regulators, the BRG1/BRM associated factor (BAF) complex. “Our lead clinical assets, which target activity of components of the multi-subunit BAF chromatin remodeling complex, include potential treatments in Phase I trials for uveal melanoma and acute myeloid leukemia/myelodysplastic syndromes,” she says.

Learning more about the epigenetic drivers of molecular changes in cancer could also fine tune treatments to specific patients. “One of the most interesting recent advances in the field of epigenetics is the improved understanding of the high prevalence of genetic mutations in epigenetic regulators in cancer,” says Ho Man Chan, PhD, head of epigenetics, R&D, AstraZeneca, which is headquartered in Cambridge, U.K. “At AstraZeneca, we are combining this understanding with the application of functional genomic CRISPR screens to identify new drug targets and new patient segments, and to develop the next wave of precision medicines.”

In addition, epitranscriptomic changes might be addressed to reduce drug resistance. In 2020, for example, a team of scientists working with Chang Zou, MD, PhD, of Shenzhen People’s Hospital in Guangdong, China, wrote: “Epitranscriptomics and epiproteomics are crucial in cell proliferation, migration, invasion, and epithelial–mesenchymal transition. In recent years, epitranscriptomic and epiproteomic modification has been investigated on their roles in overcoming drug resistance.”⁹

To effectively treat a cancer, oncologists also need tools that assess the risk of the disease, which is particularly problematic in prostate cancer. “Current clinicopathological measures are imperfect predictors of disease progression,” says Clark. So, she and her colleagues searched for new prognostic biomarkers. As a result, she says, they created “detailed methylome maps of non-lethal and lethal prostate cancer.”¹⁰ Clark adds: “Inclusion of our DNA methylation biomarkers with existing clinicopathological measures improves prognostic models of prostate cancer mortality, and holds promise for clinical application.”

Stopping the spread

If there’s a mantra for today’s cancer treatment, it could be: Early detection changes outcomes. Among most people, that mantra is countered by the fear of hearing that a cancer has metastasized to other tissues. There’s good reason for such a fear. According to the U.S. National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program, data from 2012–2018 showed that the five-year survival rate for female breast cancer was 99.1% when diagnosed while it was still local to the breast tissue, but that rate dropped to 30% for a diagnosis of metastatic breast cancer.¹¹

As Qin Yan, PhD, director of the Center for Epigenetics and Biomarkers in the department of pathology at Yale School of Medicine in New Haven, CT, says, “Tumor metastasis, or spread to distant vital organs, is the major cause of cancer-related death.”

Yan and his colleagues identified one epigenetic driver of breast-cancer metastasis called WDR5.12 “We combined in vivo and in vitro loss-of-function screens to identify WDR5 as an important druggable regulator for tumor growth and lung metastasis in a triple-negative breast cancer,” Yan explains.

Also, Yan’s team discovered several features of WDR5’s role in metastasis. “WDR5 promotes global translation rates by enhancing ribosomal protein expression,” Yan explains. Based on this knowledge, the scientists showed that targeting WDR5 along with inhibiting mTOR—a protein activated in some cancers and known as the mammalian target of rapamycin, which is an antitumor drug—“effectively reduces tumor cell growth and metastasis,” Yan says. “As new therapeutic strategies for triple-negative breast cancer are urgently needed, this study provides a novel therapeutic strategy that may improve clinical management of this patient population.”

Repairing or preventing the problem

As scientists learn more about the causes of cancer and treatments that employ new mechanisms, the potential for even bigger successes gain attention. For example, Daniels asks: “Will we be able with targeted therapies to not just selectively kill cancer cells driven by aberrant chromatin signatures, but could we reprogram them back to a healthy state?”

So, instead of just blocking an ongoing pathway causing cancer, maybe scientific research will unveil ways to stop the cancer and repair the damage. “This paradigm shift towards restorative treatment would leverage the reversible and dynamic nature of epigenetic modifications, which could lead to longer lasting and more sustainable outcomes,” Daniels explains.

Beyond treatment, scientists search for the ultimate objective, which is preventing cancer. For example, Baylin wonders what role methylation plays in the creation of cancer. So far, all he can say is: “It turns out there’s a complex network of events.”

As Clark puts it, “It’s the chicken-and-egg question: What first initiates the alterations in the epigenetic landscape in cancer?” Answering that question requires an understanding of the mechanisms at the very beginning of these diseases. “Does the loss of gene expression cause localized gain in DNA methylation and addition of chromatin repressive marks at gene promoters or conversely does the aberrant gain of promoter DNA methylation cause chromatin remodeling and thereby gene inactivation to drive cancer growth?” Clark asks. So far, no one knows.

Finding the very first triggers of cancer will not be an easy task. “We do not know for sure the culprit causing the epigenetic chaos of human tumors,” Esteller says. “Despite the finding that there are mutations in many epigenetic modifiers, many times there are shifts in the normal DNA methylation and histone modification profiles without a clear upstream cause.” Nonetheless, exploring upstream causes that spawn cancer could unveil many advances. “If we knew these mechanisms better, we could maybe design improved prevention strategies and new first-in-class, out-of-the-box epigenetic drugs,” Esteller says.

Goals worth pursuing

Part of understanding the mechanisms behind cancer could arise from finer-grained analysis, such as single-cell epigenetics. “It is worth noting the eruption of new technologies to determine epigenetic status at the single-cell level that can be relevant to determine cancer heterogeneity and the emergence of chemotherapy-resistant clones,” Esteller says. Nonetheless, he and his colleagues noted that making the most of these data depends on developing new computational tools.¹³

Other scientists also see the value of single-cell approaches. For example, Chan points out that “we still have more work to do to build a comprehensive view of the epigenomic profile of cancer cells in patients, before and after treatment,” but “a gap in knowledge exists due to technology limitations and high cost.” He believes that gap will soon be narrowed. As he says, “Recent advances in single-cell sequencing technologies and sample preparation techniques, and the ability to perform epigenomic sequencing more affordably, is likely to change this in the next few years.”

Other advances could come from applying better approaches to computation when analyzing clinical trials. In analyzing patients that a trial helped or didn’t, Baylin suggests looking deeper into the data. “We need to understand who the patients are—not only what their epigenetic changes are but the genetic background of the tumors,” he says. “That is becoming very important to this too, because there may be certain genetic backgrounds and certain immune signatures that are involved in an outcome.”

Beyond tumors themselves, scientists hope to learn more about their immediate surroundings, known as the tumor microenvironment. As Yan says, “Little is known about how the epigenome of the tumor microenvironment is regulated during disease progression and cancer treatment.” Learning more about those mechanisms, however, could lead to better treatments. As Yan notes, understanding the microenvironment “will be critical for epigenetics-directed therapeutic strategies, which are mainly characterized for their effects on tumor cells.”

The range of questions that remain about the connections between cancer and epigenetics spread as far as the field itself. Based on information related to DNA methylation, other epigenetic mechanisms, and beyond, scientists hope to learn more about the start of cancer, why it grows, and how to treat it or even prevent and intercept it. Baylin notes that approaches based on molecular understanding to personalize or develop precision-type therapy strategies are critical for the future potential of epigenetic therapy.

References

1. S. National Cancer Institute. The genetics of cancer. www.cancer.gov/about-cancer/causes-prevention/genetics#. (Last updated August 17, 2022.).
2. S. Centers for Disease Control and Prevention. What is epigenetics? www.cdc.gov/genomics/disease/epigenetics.htm#. (Last reviewed August 15, 2022.).
3. Davalos, V., Esteller, M. Cancer epigenetics in clinical practice. CA: A Cancer Journal for Clinicians. acsjournals.onlinelibrary.wiley.com/doi/10.3322/caac.21765 (2022).
4. Chen, S., Xie, P., Cowan, M., et al. Epigenetic priming enhances antitumor immunity in platinum-resistant ovarian cancer. The Journal of Clinical Investigation 132(14):e158800 (2022).
5. Chiappinelli, K.B., Strissel, P.L., Desrichard, A., et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162(5):974–986 (2015).
6. Roulois, D., Yau. H.L., Singhania, R., et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts Cell 162(5):961–973 (2015).
7. Topper, M.J., Vaz, M., Chiappinelli, K.B., et al. Epigenetic therapy ties MYC depletion to reversing immune evasion and treating lung cancer. Cell 171(6):1284–1300.e21 (2017).
8. Orsolic, I., Carrier, A., Esteller, M. Genetic and epigenetic defects of the RNA modification machinery in cancer. Trends in Genetics 39(1):74–88 (2023).
9. Song, H., Liu, D., Dong, S., et al. Epitranscriptomics and epiproteomics in cancer drug resistance: therapeutic implications. Signal Transduction and Targeted Therapy 5, article number: 193 (2020).
10. Pidsley, R., Lam, D., Qu, W., et al. Comprehensive methylome sequencing reveals prognostic epigenetic biomarkers for prostate cancer mortality. Clinical and Translational Medicine 12(10) :e1030 (2022).
11. S. National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program. Cancer Stat Facts: Female Breast Cancer. seer.cancer.gov/statfacts/html/breast.html
12. Cai, W.L., Chen, J.F-Y., Chen, H., et al. Human WDR5 promotes breast cancer growth and metastasis via KMT2-independent translation regulation. eLife 11:e78163 (2022).
13. Casado-Pelaez, M., Bueno-Costa, A., Esteller, M. Single cell cancer epigenetics. Trends in Cancer 8(10);820–838 (2022).

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