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  • Review Article
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Beyond transcription factors: how oncogenic signalling reshapes the epigenetic landscape

Nature Reviews Cancer volume 16, pages 359–372 (2016)Cite this article

Subjects

Key Points

  • Alterations in the epigenetic landscape are a hallmark of human cancer. Cancer-associated changes in the covalent modifications of DNA and histones may arise from mutations in, or the altered expression of, chromatin modifiers and/or non-coding RNAs. Recent studies show that the interplay between upstream signalling pathways and chromatin modifications represents an important mechanism controlling the cancer epigenome.

  • Kinase signalling pathways can modify the epigenome via direct phosphorylation of histones or chromatin modifiers, leading to changes in chromatin structure and gene expression. These pathways can be hijacked by oncogenic mutations to aberrantly modulate chromatin modifications. Oncogenic signalling pathways can also contribute to cancer-specific methylation patterns by controlling global DNA methyltransferase activity or the accessibility of certain regulatory elements to DNA methylation.

  • Histone modifications are involved in various cellular processes, including transcription activation, apoptosis, DNA repair and mitotic chromatin condensation. The dynamic process of phosphorylation (for example, at histones H3S10 and H3S28) can impair the deposition of potentially more stable methyl marks on adjacent lysine residues; such crosstalk can amplify the influence of signalling pathways on chromatin structure.

  • Chromatin modifiers, such as enhancer of zeste homologue 2 (EZH2), BMI1, p300 and CREB binding protein (CBP), are phosphorylated by multiple upstream signalling kinases, indicating that they can function as points of convergence for these signalling pathways. The end result of these phosphorylation events can vary depending on their site-specific and cell type-specific context.

  • The DNA damage response represents a major signalling pathway that alters chromatin structure via the phosphorylation of histones and histone modifiers. The decision of cells to undergo cell cycle arrest and repair damaged DNA or undergo cell death reflects the integration of various upstream signals.

  • The interplay between signalling pathways and the epigenome may have important implications for therapeutic strategies for cancer. Treating tumour cells with kinase inhibitors may not be sufficient to restore the deregulated gene expression programmes that are found in these cells. Combining kinase inhibitors with epigenetically focused therapies may more effectively reverse the epigenetic features that maintain the transformed phenotype in cancer cells, leading to improved patient outcomes.

Abstract

Cancer, once thought to be caused largely by genetic alterations, is now considered to be a mixed genetic and epigenetic disease. The epigenetic landscape, which is dictated by covalent DNA and histone modifications, is profoundly altered in transformed cells. These abnormalities may arise from mutations in, or altered expression of, chromatin modifiers. Recent reports on the interplay between cellular signalling pathways and chromatin modifications add another layer of complexity to the already complex regulation of the epigenome. In this Review, we discuss these new studies and how the insights they provide can contribute to a better understanding of the molecular pathogenesis of neoplasia.

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Figure 1: Histone modifications regulated by the JAK–STAT pathway.
Figure 2: Regulation of Polycomb group protein repressive complexes by signalling pathways.
Figure 3: The extensive regulation of CBP and p300 histone acetyltransferase activity by signalling kinases.
Figure 4: The DNA damage response modulates chromatin modifications.
Figure 5: Oncogenic signalling regulates DNA methyltransferase 1 activity.
Figure 6: The epigenetic memory of signalling.

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Acknowledgements

The authors thank F.-c. Yang and L. Morey for their helpful advice, and D. Prou for her assistance with manuscript preparation. The S.D.N. laboratory is supported by National Cancer Institute Grant RO1 CA166835-01, F.L. is supported by an American Cancer Society Institute Research Grant Pilot Project Award, and W.L. is supported by National Natural Science Foundation of China Grant 81470334.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Miami, Miami, 33136, Florida, USA

    Fan Liu & Stephen D. Nimer

  2. Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, 33136, Florida, USA

    Fan Liu & Stephen D. Nimer

  3. Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/School of Medicine, Shanghai Jiao Tong University, 200031, Shanghai, China

    Lan Wang

  4. State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China

    Lan Wang

  5. Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, 10065, New York, USA

    Fabiana Perna

  6. Department of Internal Medicine, University of Miami, Miller School of Medicine, Miami, 33136, Florida, USA

    Stephen D. Nimer

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  1. Fan Liu
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Glossary

Myeloproliferative neoplasms

(MPNs). A group of diseases that affect normal blood cell production in the bone marrow, which manifests as an overproduction of one or more blood cell types (red cells, white cells or platelets).

Genomic imprinting

An epigenetic phenomenon that results in a mono-allelic, parental-specific expression pattern of a subset of genes. For example, if the paternal allele of a certain gene is imprinted, and thereby silenced, then only the maternal allele of this gene can be expressed.

CpG island

A DNA region with at least 200 base pairs, and a CG percentage of more than 50%. Methylation of the CpG sites within the gene promoter can lead to gene silencing.

Transposable elements

(TEs). Small pieces of DNA that can move within the genome. TEs can modify DNA by causing mutations, inducing or repressing nearby genes, or altering levels of protein synthesis.

Immediate-early genes

A class of genes that are quickly inducible in response to infection or extracellular signals and do not require new protein synthesis. They consist of diverse proteins including transcription factors and cytokines and often regulate cell growth and differentiation.

Myelodysplastic syndrome

(MDS). A haematological medical condition, also known as myelodysplasia, that is characterized by ineffective production of myeloid lineage blood cells and a disorder of the haematopoietic stem cells in the bone marrow. Patients with MDS are at high risk of progression to leukaemia.

Oesophageal squamous cell carcinoma

A type of cancer that begins in the flat squamous cells lining the oesophagus. Smoking and heavy alcohol use increase the risk of this disease.

Lung sarcomatoid carcinoma

A rare and heterogeneous group of aggressive lung carcinomas, with histological features that resemble those of a sarcoma.

Desmoplastic medulloblastoma

A histological subtype of medulloblastoma, the most common malignant brain tumour in children, that is characterized by nodular structures that contain reticulin-free zones surrounded by densely packed highly proliferative cells.

Non-Hodgkin lymphomas

Lymphomas other than Hodgkin disease, classified as nodular or diffuse depending on the tumour pattern and cell type.

S-adenosylmethionine

A universal methyl group donor that is critical for the synthesis of hormones, phospholipids and macromolecules in the cell. An important cofactor for methyltransferase proteins.

Rubinstein–Taybi syndrome

(RTS). A condition characterized by short stature, moderate to severe intellectual disability, distinctive facial features and broad thumbs and first toes. Mutations in the genes CREBBP and EP300 (encoding CREB binding protein (CBP) and p300, respectively) are seen in some people with this condition.

von Hippel–Lindau protein

An E3 ubiquitin protein ligase that functions as part of the VCB–CUL2 complex, and is classified as a tumour suppressor.

Fanconi anaemia

(FA). A rare inherited disease that results from mutations in a subset of genes involved in the DNA repair response. Patients with FA generally develop severe anaemia and may have physical abnormalities. They are at high risk of developing certain types of cancer.

Ataxia telangiectasia

(A-T). An inherited disease that affects several body systems, including the immune system and the central nervous system; patients with A-T have a high rate of cancer.

Bloom syndrome

An inherited disorder that causes growth defects, chromosomal instability and a predisposition to cancer. This disorder is induced by mutations in BLM, which encodes a RecQ helicase, a family of enzymes that maintain DNA integrity.

Epithelial–mesenchymal transition

The process by which epithelial cells lose cell–cell junctions and baso-apical polarity and acquire plasticity, mobility, invasive capacity, stem-like characteristics and resistance to apoptosis.

Oestrogen receptor

(ER). The intracellular receptor activated by the hormone oestrogen. Upon ligand binding, the ER can translocate into the nucleus and bind to DNA to regulate gene expression. The ER is overexpressed in ∼70% of breast cancers

Progesterone receptor

The intracellular receptor activated by the steroid hormone progesterone, which is often overexpressed in breast cancer.

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Liu, F., Wang, L., Perna, F. et al. Beyond transcription factors: how oncogenic signalling reshapes the epigenetic landscape. Nat Rev Cancer 16, 359–372 (2016). https://doi.org/10.1038/nrc.2016.41

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