Epigenetic drivers of tumourigenesis and cancer metastasis

Abstract

Since the completion of the first human genome sequence and the advent of next generation sequencing technologies, remarkable progress has been made in understanding the genetic basis of cancer. These studies have mainly defined genetic changes as either causal, providing a selective advantage to the cancer cell (a driver mutation) or consequential with no selective advantage (not directly causal, a passenger mutation). A vast unresolved question is how a primary cancer cell becomes metastatic and what are the molecular events that underpin this process. However, extensive sequencing efforts indicate that mutation may not be a causal factor for primary to metastatic transition. On the other hand, epigenetic changes are dynamic in nature and therefore potentially play an important role in determining metastatic phenotypes and this area of research is just starting to be appreciated. Unlike genetic studies, current limitations in studying epigenetic events in cancer metastasis include a lack of conceptual understanding and an analytical framework for identifying putative driver and passenger epigenetic changes. In this review, we discuss the key concepts involved in understanding the role of epigenetic alterations in the metastatic cascade. We particularly focus on driver epigenetic events, and we describe analytical approaches and biological frameworks for distinguishing between "epi-driver" and "epi-passenger" events in metastasis. Finally, we suggest potential directions for future research in this important area of cancer research.

MEIS1 knockdown may promote differentiation of esophageal squamous carcinoma cell line KYSE‐30

“…Malignancy is a complex heterogeneous illness introduced through accumulation of different damaging genetic and epigenetic alterations in tumor cells. Notably, disruption of various signaling networks and multiple molecular mechanisms involved in tumor onset and development can lead to extensive deregulation of gene expression profiles in human cancers (Beerenwinkel, Schwarz, Gerstung, & Markowetz, ; Chatterjee et al, ; Du & Che, ). Among identified genetic changes in the cancer etiology, abnormal expression of different gene categories such as tumor suppressors, oncogenes, DNA repair genes, stem cell‐related surface markers and cancer stem cells (CSCs) specific transcriptional factors (TFs), can be noted as leading cause of tumorigenesis (Sadikovic, Al‐Romaih, Squire, & Zielenska, ; Zhao, Li, & Zhang, ).…”

Mutated EPHA2 is a target for combating lymphatic metastasis in intrahepatic cholangiocarcinoma

“…Carcinogenesis and metastasis are the consequences of the induction of genetic and/or epigenetic alternations. 24,25 A better understanding of the genomic alternations that drive cancer development, especially the metastasis process, is imperative for improving the current therapeutic options and patients' outcome. Recently a large cohort study demonstrated that the metastatic cancers is a highly heterogeneous disease at the genetic, transcriptomic, and microenvironment levels.…”

Depletion of nuclear pore protein NUP210 suppresses metastasis through heterochromatin-mediated disruption of tumor cell mechanical response

“…This reporter expresses tdTomato protein fused to both a nuclear localization signal (NLS) and nuclear export signal (NES), resulting in shuttling between the cytoplasm and nucleus. Transfection of this reporter into Nup210 knockdown 4T1 cells with or without the nuclear export inhibitor leptomycin B showed no significant differences in nucleocytoplasmic transport of the reporter protein 11 ( Supplementary Fig. 4b).…”

“…Epigenetic changes such as DNA methylation, histone modification, and chromatin remodeling can also affect gene expression in cancer 10 . Epigenetic silencing of tumor suppressor genes or activation of oncogenes has been implicated in cancer progression 11,12 . These genes can be silenced or activated through widespread alterations in chromatin accessibility due to the gain or loss of heterochromatin regions.…”