Epigenetic regulation of cancer stemness

Abstract

Gene expression is finely controlled by the abundance and activation status of transcription factors and their regulators, as well as by a number of reversible modifications of DNA and histones that are commonly referred to as epigenetic marks. Such alterations (i.e., methylation, acetylation, and ubiquitination) are catalyzed by an array of dedicated enzymes with antagonistic activity, including methyltransferases and demethylases, acetyltransferases and deacetylases, as well as ubiquitin ligases and deubiquitinating enzymes. The epigenetic control of transcription is critical not only for embryonic and postembryonic development but also for the preservation of homeostasis in all adult tissues. In line with this notion, epigenetic defects have been associated with a variety of human disorders, including (but not limited to) congenital conditions as well as multiple hematological and solid tumors. Here, we provide an in-depth discussion of the impact of epigenetic alterations on cancer stemness, i.e., the ability of a small population of poorly differentiated malignant cells to (1) self-renew while generating a more differentiated progeny, and (2) exhibit superior tumor initiating/repopulating potential along with exceptional plasticity and improved resistance to environmental and therapy-elicited stress. Moreover, we critically evaluate the potential and limitations of targeting epigenetic modifiers as a means to eradicate cancer stem cells for therapeutic purposes.

Fig. 1

Major epigenetic mechanisms of transcriptional regulation. Multiple epigenetic modifications regulate transcription. DNA methylation, which is catalyzed by DNA methyltransferases (DNMTs) and reversed by Tet methylcytosine dioxygenases (TETs), typically represses transcription by impairing transcription factor (TF) binding. In contrast, histone posttranslational modifications (PTMs), including acetylation, methylation, and ubiquitination, modulate chromatin structure and transcriptional accessibility. Histone acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), and promotes gene expression by opening chromatin. In contrast, the methylation of specific histone residues, which is regulated by lysine histone methylases (KTMs) and lysine demethylases (KDMs), has functional consequences that are influenced by the position of the residue and the degree of methylation. Similarly, histone ubiquitination, which is catalyzed by E1-activating-E2 conjugating-E3 ligase systems, including polycomb repressive complex 1 (PRC1), and is reversed by deubiquitinating enzymes (DUBs), with histone 2A (H2A) and H2B as the main targets, regulates gene expression in a context-dependent manner. Notably, these marks not only affect local promoter activity but also regulate distal elements such as enhancers. Moreover, epigenetic modifications often act in concert, with extensive crosstalk between DNA methylation and histone PTMs, either synergistically or antagonistically influencing gene expression, partly through the recruitment of reader proteins and chromatin remodeling complexes

Fig. 2

CSC features influenced by epigenetic processes. Epigenetic mechanisms contribute to the maintenance of cancer stem cell (CSC) identity by: (1) enabling an indefinite proliferative capacity; (2) preserving an undifferentiated cellular state; (3) promoting tumor initiation and repopulation by supporting asymmetric division, which allows CSCs to simultaneously self-renew and generate differentiated progeny, thereby replenishing the tumor mass; (4) increasing treatment resistance through mechanisms such as quiescence, enhanced DNA damage repair, efficient reactive oxygen species (ROS) detoxification, and limited apoptotic sensitivity; and (5) driving immune evasion mechanisms, including defective antigen presentation, immunosuppressive cytokine production, and the upregulation of coinhibitory immune checkpoints, which allow CSCs to escape immunosurveillance. CTL cytotoxic T lymphocyte, CTL_EX exhausted CTL, T_REG regulatory T cell

Fig. 3

Epigenetic regulation of CSC-related oncogenesis and tumor progression. DNA methylation, histone methylation, histone acetylation, and histone ubiquitination regulate a number of genetic programs that sustain the tumor-forming and repopulating capacities of cancer stem cells (CSCs), including programs that: (1) enable and preserve self-renewal, (2) prevent cellular differentiation, (3) activate oncogenic signaling and/or inactivate cancer cell-intrinsic oncosuppression, (4) deregulate cell cycle control and apoptotic cell death, and (5) promote local invasiveness and metastatic dissemination. This figure summarizes findings from tumors with a recognized CSC-driven cellular hierarchy, including acute and chronic myeloid leukemia, glioblastoma, colorectal carcinoma, and breast cancer

Fig. 4

Epigenetic regulation of CSC self-renewal. DNA methylation, histone methylation, histone acetylation, and histone ubiquitination are implicated in the control of genetic programs regulating the preservation of self-renewal in cancer stem cells (CSCs). These programs involve not only the epigenetic activation of pluripotency factors such as SOX2 and NANOG but also (1) the activation of signal transduction cascades that support stemness, such as WNT/β-catenin and NOTCH signaling, and (2) the repression of gene sets promoting cellular differentiation. This figure summarizes findings from tumors with a recognized CSC-driven cellular hierarchy, including acute and chronic myeloid leukemia, glioblastoma, colorectal carcinoma, and breast cancer. ↑, increased activity or expression; ↓, decreased activity or expression. Proteins listed in red lack recognized catalytic activity but regulate the functions of bona fide epigenetic modifiers (black)

Fig. 5

Epigenetic plasticity as a driver of cancer stemness. A number of plasticity programs sustain cancer stem cell (CSC) properties and tumor evolution through epigenetic mechanisms. These programs promote: (1) dedifferentiation to a stem-like state, whereby differentiated cancer cells revert to CSCs in response to oncogenic or environmental cues, including therapy, via chromatin remodeling and activation of pluripotency-associated transcriptional networks; (2) drug-tolerant persistence, in which a subpopulation of cancer cells survives therapy by entering a slow-cycling, stem-like state, forming a reservoir that seeds for relapse and resistance; (3) epithelial‒mesenchymal plasticity (EMP), referring to reversible transitions across hybrid epithelial‒mesenchymal transition (EMT) and mesenchymal‒epithelial transition (MET) states associated with stem‒like traits and increased metastatic potential; and (4) CSC heterogeneity, referring to the dynamic transitions across CSC states, contributing to tumor heterogeneity and adaptation

Fig. 6

Targeting epigenetic regulators in cancer stem cells. Multiple epigenetic modifiers can be pharmacologically targeted to preferentially eradicate cancer stem cells (CSCs), either as standalone targets or alongside conventional treatments (CTs) as a means to increase therapeutic efficacy. These include enzymes or factors involved in: (1) DNA methylation, such as DNMT1; (2) histone methylation, such as EZH2 or KDM1A; (3) histone acetylation, such as CREBBP, EP300, and multiple histone deacetylases (HDACs); and (4) histone ubiquitination, such as BMI1. However, targeting epigenetic regulators poses key challenges, including toxicity to normal stem cells, the emergence of drug resistance, and incomplete CSC elimination due to tumor plasticity, implying that safe and effective therapeutic strategies may require tumor-specific and combination approaches