Cancer, metastasis, and the epigenome

Abstract

Cancer is the second leading cause of death worldwide and disease burden is expected to increase globally throughout the next several decades, with the majority of cancer-related deaths occurring in metastatic disease. Cancers exhibit known hallmarks that endow them with increased survival and proliferative capacities, frequently as a result of de-stabilizing mutations. However, the genomic features that resolve metastatic clones from primary tumors are not yet well-characterized, as no mutational landscape has been identified as predictive of metastasis. Further, many cancers exhibit no known mutation signature. This suggests a larger role for non-mutational genome re-organization in promoting cancer evolution and dissemination. In this review, we highlight current critical needs for understanding cell state transitions and clonal selection advantages for metastatic cancer cells. We examine links between epigenetic states, genome structure, and misregulation of tumor suppressors and oncogenes, and discuss how recent technologies for understanding domain-scale regulation have been leveraged for a more complete picture of oncogenic and metastatic potential.

Keywords: Chromatin state; EMT; Epigenetic; Metastasis; Topology; Transcription.

Fig. 1

Oncogenic loss of checkpoint and growth control. (Left) A p53 tetramer mediates G1/S checkpoint and apoptotic responses to DNA damage and other stressors through transcription of p53 response element (p53RE) target genes. Binding of p14ARF (CDKN2A alternate reading frame) to MDM2 inhibits p53 ubiquitination and degradation. (Middle) Rb promotes G1/S progression through E2F transcription factors, transcribing cyclins and activating cylin-dependent kinases that in turn activate Rb. Rb/PcG complexes also repress transcription through H3K27me3 deposition from Polycomb group complexes (PcG). (Right) A phosphorylation cascade proceeds from Ras through either B-Raf, MEK, and MAPK/ERK proteins, or PI3K, AKT, and NF-$\kappa$B, activating growth, proliferation, and immune responses. (Bottom) Common alterations that disrupt checkpoint function, increase proliferative signals, or affect cell cycle regulation and growth through alterations in p53, Rb, or Ras signaling, promoting oncogenesis

Fig. 2

Origins of genomic instability. Defects in DNA damage recognition and repair, replication stress, copy number alteration, and reduced replication fidelity each contribute to genomic instability, which is self-perpetuating and exacerbated through rounds of cell division

Fig. 3

Phenotypic malleability and dedifferentiation. (Left) Wnt binding to Frizzled and LRP5/6 receptors triggers phosphorylation of LRP5/6 by GSK3 and CK1, which together with the recruitment of Dishevelled to Frizzled, binds Axin to the plasma membrane. This also sequesters the destruction complex to the dimerized receptors, stabilizing $\beta$-catenin and allowing its translocation to the nucleus to promote cell proliferation. (Right) SOX2 can be activated through various sources, including the Ras/Raf pathway or more directly though STAT3. SOX2/Oct4 complexes promote stem phenotypes and dedifferentiation by activating core pluripotency transcription factors

Fig. 4

The nucleosome, consisting of about 146 bp of DNA wrapped around the histone octet. Histone tails protruding from the core particle serve as sites for covalent modification that alters gene expression. Structure image produced using PDB (ID: 7VZ4)

Fig. 5

Chromatin state regulation and misregulation in cancer. Nuclear chromatin can be broadly clustered into domains of euchromatic (left) and heterochromatic character, divided into facultative (middle) and constitutive (right) classes. (Left) Euchromatic regions contain transcriptionally competent genes with high levels of enhancer H3K4me1 and H3K27ac, high H3K4me3 bounding transcription start sites (TSS), and repressive promoter H3K27me3 levels that depend on local regulation. H3K36me3 marks recently transcribed genes to suppress intragenic transcription. (Middle) Facultative heterochromatin is characterized by broader H3K27me3 domains established by PRC2, bounded by H3K36me2/3, and H2AK119 ubiquitination by H3K27me3-directed PRC1. (Right) Constitutive heterochromatin features high H3K9me3 and consequent HP1 binding adjacent nucleosomes to direct chromatin compaction, along with domains tethered to the nuclear lamina (LADs). DNA methyltransferases stabilize silencing and compaction of facultative and constitutive heterochromatic domains. (Bottom) Loss of regulated transitions between these states are common in oncogenic transformation, with representative examples shown

Fig. 6

Scales of genome structural regulation. Chromosome territories divide the nucleus into a top level regional organization. Beyond this, partitions emerge of largely self-interacting compartments of euchromatic (compartment A) or heterochromatic (compartment B) character, associated with domain-level repression or activation. Topological domains represent individual regions of enriched interactions. At the smallest scales, misregulation can occur through loss or gain of architectural protein interactions and enhancer-promoter contacts

Fig. 7

Cell state deregulation, migration, and metastasis. Pre-metastatic cells lose epithelial features and silence expression of epithelial biomarkers such as E-cadherin in favor of a more aggressive mesenchymal phenotype, characterized by expression of vimentin and N-cadherin and often accompanied by stem cell markers. Loss of cellular identity and adhesion promotes migration, lymph node engraftment, and development of immune-tolerant secondary tumors