Chromatin Dynamics in Digestive System Cancer: Commander and Regulator

Abstract

Digestive system tumors have a poor prognosis due to complex anatomy, insidious onset, challenges in early diagnosis, and chemoresistance. Epidemiological statistics has verified that digestive system tumors rank first in tumor-related death. Although a great number of studies are devoted to the molecular biological mechanism, early diagnostic markers, and application of new targeted drugs in digestive system tumors, the therapeutic effect is still not satisfactory. Epigenomic alterations including histone modification and chromatin remodeling are present in human cancers and are now known to cooperate with genetic changes to drive the cancer phenotype. Chromatin is the carrier of genetic information and consists of DNA, histones, non-histone proteins, and a small amount of RNA. Chromatin and nucleosomes control the stability of the eukaryotic genome and regulate DNA processes such as transcription, replication, and repair. The dynamic structure of chromatin plays a key role in this regulatory function. Structural fluctuations expose internal DNA and thus provide access to the nuclear machinery. The dynamic changes are affected by various complexes and epigenetic modifications. Variation of chromatin dynamics produces early and superior regulation of the expression of related genes and downstream pathways, thereby controlling tumor development. Intervention at the chromatin level can change the process of cancer earlier and is a feasible option for future tumor diagnosis and treatment. In this review, we introduced chromatin dynamics including chromatin remodeling, histone modifications, and chromatin accessibility, and current research on chromatin regulation in digestive system tumors was also summarized.

Keywords: chromatin dynamics; clinical trials; digestive system tumor; epigenetics; targeted therapy.

Figure 1

Chromatin dynamics in genome: chromatin accessibility, histone modification, DNA methylation, and chromatin remodeling. DNA entangles histones (H2A, H2B, H3, and H4) to form nucleosomes, the basic functional unit of chromatin. Nucleosome occupancy in the genome, histone modifications, DNA methylation, and chromatin remodelers leads to alternations in chromatin accessibility, which regulates processes such as gene transcription and translation. Histone modifications include histone methylation, acetylation, ubiquitination, phosphorylation, and SUMOylation, with histone-modifying enzymes and associated gene expression abnormalities playing a major role in these processes. Chromatin remodeling complexes include SWI/SNF, ISWI, CHD, and IN80.

Figure 2

Mechanisms of chromatin alterations regulating digestive system tumors. Histone modifications, chromatin remodelers, and DNA methylation affect critical signal pathways not only by altering gene expression levels but also by regulating chromatin accessibility.

Figure 3

Epigenetic-related gene mutations in digestive system cancers. Frequency of mutations in epigenetically critical genes in digestive system tumors (esophageal carcinoma, gastric carcinoma, hepatocellular carcinoma, pancreatic adenocarcinoma, colorectal adenocarcinoma, and cholangiocarcinoma) is shown as a heatmap. The mutation rates of these genes are high in esophageal carcinoma, gastric carcinoma, and colorectal adenocarcinoma, while pancreatic adenocarcinoma and hepatocellular carcinoma have low mutation rates.