The roles of epigenetics in cancer progression and metastasis

Abstract

Cancer metastasis remains a major clinical challenge for cancer treatment. It is therefore crucial to understand how cancer cells establish and maintain their metastatic traits. However, metastasis-specific genetic mutations have not been identified in most exome or genome sequencing studies. Emerging evidence suggests that key steps of metastasis are controlled by reversible epigenetic mechanisms, which can be targeted to prevent and treat the metastatic disease. A variety of epigenetic mechanisms were identified to regulate metastasis, including the well-studied DNA methylation and histone modifications. In the past few years, large scale chromatin structure alterations including reprogramming of the enhancers and chromatin accessibility to the transcription factors were shown to be potential driving force of cancer metastasis. To dissect the molecular mechanisms and functional output of these epigenetic changes, it is critical to use advanced techniques and alternative animal models for interdisciplinary and translational research on this topic. Here we summarize our current understanding of epigenetic aberrations in cancer progression and metastasis, and their implications in developing new effective metastasis-specific therapies.

Keywords: cancer metastasis; chromatin opening; enhancer reprogramming; epigenetics; histone modification; tumor progression.

Figure 1.. The metastatic cascade.

Top-During the metastatic progression, primary tumor (for example (e.g.,) breast cancer undergoes epigenetic changes to acquire the metastatic traits to form distant metastases (e.g., lung, brain, and bone metastasis). Bottom-The cancer cells at the primary site acquire the ability to invade and migrate through the blood vessels, survive in the circulation, extravasate the blood vessels, settle down at the distant microenvironment, and proliferate to form metastases.

Figure 2.. The epigenetic landscape and epigenetic control.

(A) Chromatin states can be switched between “opened” (Euchromatin) and “closed” (Heterochromatin) states to maintain gene activation or gene silencing, respectively. Many types of epigenetic regulations act in concert to maintain certain chromatin state, including histone modifications, transcriptional regulation, enhancer reprogramming, DNA methylation, non-coding RNA regulation, and RNA modifications. The opened chromatin state allows the binding of transcription factors to the promoter and enhancer regions of a genome locus to drive gene expression. (B) The epigenetic control is reversible. Each type of modification can be added to the modification site through a “writer” protein, removed by an “eraser” protein, and can be recognized by a “reader” protein through a specific interacting domain. Chromatin remodelers are a class of proteins that are able to restructure chromatin packaging.

Figure 3.. Transcription factors regulate chromatin opening in cancer metastasis.

(A) IL6 induction activates transcription factor STAT3 through hijacking the enhancer element of FOXA1 and ER, thereby drives the expression of STAT3 targets and metastasis. (B) Upregulation of NFIB drives the chromatin accessibility in small cell lung cancer to activate pro-metastatic neuronal genes and metastasis. (C) Alteration of chromatin accessibility driven by downregulation of NKX2.1 and upregulation of RUNX2 switches the transcription program to extracellular remodeling gene program and activates lung cancer metastasis. (D) Differential activation of chromatin states at specific locus leads to binding of specific transcription factors that regulate organotropic metastasis.

Figure 4.. Control of cancer metastasis by histone modifiers.

(A) EZH2 promotes cancer metastasis in prostate cancer by silencing DAB2IP with the addition of H3K27me3 on the nucleosome. (B) Loss of PRC2 complex de-represses its target CXCR4, thereby promotes metastasis in ccRCC. (C) LSD1 suppresses breast cancer metastasis by removing H3K4 methylation to silence TGFβ1. (D) KDM4A promotes head and neck SCC metastasis by activating the expression of JUN and FOSL1 through removing the H3K9me3 mark. The activation of JUN further enhanced its transcription through binding to its promoter AP-1 site. (E) KDM4C promotes breast cancer metastasis by removing H3K9me3 thereby activating the transcription of HIF1 target genes. The activation of HIF1 further enhanced its transcription through binding to the HIF-response element. (F) In breast cancer, the expression of KDM5A correlates with metastasis progression, and KDM5A activates its target TNC in a demethylase-independent manner. (G) The H4R3me2S modification can be read by PHF1, which recruits writer proteins PRMT5 and Cul4B-ubiquitin E3 ligase complex to silence its target E-cadherin and FBXW7, thereby suppresses metastasis. (H) ZMYD3 recruits KDM5D and recognizes the dual histone mark H3K14ac and H3K4me1. KDM5D then erases the methylation from histone to suppress metastasis-linked genes and metastasis progression.

Figure 5.. Enhancer reprogramming drives cancer metastasis.

(A) AR enhancer activation and amplification drives the progression of primary prostate cancer to advanced stage. (B) In pancreatic cancer, FOXA1 activates enhancers of its target to drive liver metastasis. (C) The formation of super enhancer allows the binding of NF-κB and HIF2A to drive the expression of their common target CXCR4, thereby promotes lung metastasis in ccRCC. (D) The formation of super enhancer in inflammatory ccRCC activates the expression of CXCLs to promote neutrophil infiltration thereby promotes lung metastasis.

Figure 6.. Other epigenetic mechanisms of metastasis.

(A) Asymmetrical arginine demethylation of BAF155 by PRMT4 retargets the SWI/SNF complex to the c-Myc pathway genes to drive breast cancer metastasis. (B) CAF-1 suppression reduces the incorporation of canonical histone H3.1/3.2, and increases the incorporation of H3.3 variant to increase chromatin accessibility and activates the target gene expression and metastasis. (C) E-cadherin 5’ CpG island hypermethylation silences its expression and promotes metastasis in breast cancer. (D) Promoter demethylation at SAA genes allows for the binding of NF-κB and C/EBP to activate SAAs to promote metastasis. (E) Upregulation of HOTAIR recruits PRC2 complex to silence metastasis-suppressor genes, thereby promotes metastasis. (F) PRC2 silencing of the lncRNA upstream of circRNA CDR1as decreases the expression of CDR1as, which releases its binding partner IGF2BP2 to stabilize its mRNA target, thereby promotes metastasis. (G) m6A modification increases the stabilization of ZMYM1. Increased expression of ZMYM1 recruits the LSD1 complex to silence E-cadherin, thereby promotes metastasis. (H) YTHDF3 reads m6A marks on brain metastasis-associated mRNAs, which increases the mRNA stability and activates brain metastasis phenotypes.

Figure 7.. Strategies for targeting epigenetics in metastatic diseases.

Multiple epigenetic regulators participate in cancer metastasis. These epigenetic changes are able to alter cell-intrinsic phenotypes or the tumor microenvironment, which could be targeted by specific inhibitors. (1) The step of epithelial-mesenchymal transition could be reversed by EZH2 inhibitor, WDR5 inhibitor, HDAC inhibitors, or BET inhibitor. These drugs suppress metastatic progression by decreasing the expression of genes regulating migratory capacity, cell invasiveness, and decrease the production of ECM components of cancer cells. (2) Modulating tumor microenvironment unfavored by the cancer cells could discourage metastasis seeding. Low dose DNMT inhibitor and HDAC inhibitor or CECR2 inhibitor could inhibit the production of several chemokines that attract MDSC cells, thereby suppresses premetastatic niche formation. This treatment approach could prevent the occurrence of metastatic diseases. (3) Activating the immune system could be effective in suppressing cancer growth. In metastatic cancer cells, upregulation of CECR2 promotes M2 macrophage polarization. Targeting M2 macrophage polarization with CECR2 inhibitor is able to reverse the immune suppressive microenvironment, thereby suppresses metastasis outgrowth.