ATP-dependent chromatin-remodeling complexes can reorganize and remodel chromatin and thereby act as important regulator in various cellular processes. Based on considerable studies over the past two decades, it has been confirmed that the abnormal function of chromatin remodeling plays a pivotal role in genome reprogramming for oncogenesis in cancer development and/or resistance to cancer therapy.
1. Introduction
In eukaryotes, genetic information is stored in the chromatin. Chromatin is organized into repeated units of nucleosomes, in which DNA is tightly packaged into the histone octamer. Two copies of histones (that is the core histones, H2A, H2B, H3, and H4) are linked by histone H1 and comprise the histone octamer, and the assembled histone octamers are further organized to form higher-order chromatin that has several additional chromatin-interacting proteins. Due to compositional diversity, chromatin is highly dynamic and plastic, thereby providing it with high potential to modify genome topology and to orchestrate gene regulation in many aspects of cellular processes
[1]. During DNA methylation, the complex post-translational modifications of chromatin proteins and chromatin-remodeling activity are the main heritable epigenetic characteristics
[2]. Among these, chromatin remodeling has emerged in recent years as an important regulator for the precise control of the development of tissues and organs, as well as for disease progression in living organisms.
Studies of the underlying mechanistic alterations during disease progression in chromatin remodeling have identified numerous regulatory factors, and have revealed novel mechanistic and functional insights into the relationships of chromatin-remodeling heterogeneity and disease progression, especially in development and treatment of cancer
[3]. Chromatin remodeling links the genome with its functional phenotype through several primary mechanisms: (1) ATP-dependent chromatin-remodeling complexes ensure the proper distribution of nucleosomes; (2) remodeling complexes move or eject histones to allow transcription factors to bind to DNA; and (3) remodeling complexes replace the histone with variants of the histone. Thereby, genome-wide nucleosome positioning and composition are tailored by specialized remodelers. In recent years, profound advancements have been made in understanding cancer mechanisms, providing new insights into the molecular processes underlying tumor progression and indicating novel treatment strategies. In addition, the extensively developed molecular biology techniques are allowing a new appreciation of the role of chromatin remodeling in disease development, particularly in cancer
[4].
2. Dysregulation of Chromatin-Remodeling Machines in Cancer
Chromatin can be either packed in the form of accessible euchromatin, or densely as heterochromatin
[5]. Intricately packaged chromatins must be relaxed before the functional complex can be accessed, and the molecular regulatory mechanism of chromatin accessibility is mainly observed through histone modification and ATP-dependent remodelers
[6]. Histone enzymes post-translationally modify histone tails and hence alter the atomic structure of nucleosomes to either inhibit or promote the recruitment of various chromatin-associated proteins. So far, several histone modifications have been identified as crucial regulators in cancer progression via controlling chromosomal packing, such as methylation, acetylation, phosphorylation, ADP ribosylation, ubiquitylation, SUMOylating, etc. For example, a histone acetylation-based gene signature was found to be significantly related to the prognosis of ovarian cancer
[7]. Histone methylation status can also be marked at specific sites on chromatin, such as transcriptionally repressed regions with a high H3K27me3 signal or in active regions with a rich H3K4me3 signal
[8]. It is important to note that aberrant DNA methylation was closely related to cancer development, an example of which is H3K27me3, which was found to play a paramount role in defining the tumor-promoting capacities of cancer-associated fibroblasts
[9].
ATP-dependent remodeling enzymes are other essential mediators of dynamic chromatin and utilize ATP hydrolysis to mobilize nucleosomes, thereby mediating the chromatin structure and the regulation of gene expression
[3]. According to the homology in the catalytic ATPases and associated subunits, ATP-dependent chromatin-remodeling complexes can be divided into four subfamilies: switch/sucrose non-fermentable (SWI/SNF), imitation switch (ISWI), chromodomain helicase DNA-binding (CHD) and inositol 80 (INO80) (
Figure 1A). The SWI/SNF complex contains a central ATPase domain that includes two RecA-like lobes and a conserved insertion, a SANT-associated (HSA) domain and an adjacent post-HSA domain at the N-terminus, and AT-hooks and a bromodomain at the C-terminus which bind the acetylated lysins in histone. The ISWI complex contains a central ATPase domain, an autoinhibitory N-terminal (AutoN) domain, a negative regulator of coupling (NegC) domain that flanks the ATPase domain, and a HAND–SANT–SLIDE (HSS) domain at the C-terminus that binds nucleosome and inter-nucleosome DNA. The CHD complex contains a central ATPase domain, arranged in tandem with the chromodomains at the N-terminus that bind the methylated lysins in histone, a NegC domain, and a SANT–SLIDE domain at the C-terminus. The INO80 complex contains a central ATPase domain that includes a large insertion between the RecA-like lobes and an HSA domain at the C-terminus that binds actin-related components. Among the diverse components, ATPase subunits function as motivators that display the DNA/nucleosome-dependent ATPase activity that induces nucleosome assembly and organization, chromatin access, and nucleosome editing (
Figure 1B). Each of the remodeler subfamilies contains distinct catalytic ATPases, as well as some associated subunits that collectively generate those who have the potential to form numerous complexes though combinatorial assembly
[10]. These large multi-subunit complexes commonly contain specific domains and subunits that are essential for targeting the complex to specific chromatin sites, generally via binding to DNA, modified histones or histone variants. Additionally, these large multi-subunit complexes undergo a high degree of transformation to guarantee the dynamic cellular processes needed to adapt to the changes in the internal and external environments, such as cancer proliferation signals and chemotherapy-induced damage
[11]. Therefore, a better understanding of chromatin remodeling is essential for developing new anticancer therapeutic strategies.
Figure 1. Domain organization and composition of chromatin-remodeling complex. (A) Domain organization of four chromatin remodeler complexes. Remodelers can be divided into four subfamilies according to the domain organization in the catalytic ATPases and their associated subunits. The ATPase domains in all of the remodelers are used to mobilize nucleosomes and comprise two RecA-like folds, which are separated by an insertion (yellow). Asterisk represents structural similarity. (B) The main complexes in each subfamily. The ATPase subunits, shared subunits, and variable subunits of the representative complexes in each of the four families of human chromatin remodelers.