Current understanding of epigenetics mechanism as a novel target in reducing cancer stem cells resistance

Abstract

At present, after extensive studies in the field of cancer, cancer stem cells (CSCs) have been proposed as a major factor in tumor initiation, progression, metastasis, and recurrence. CSCs are a subpopulation of bulk tumors, with stem cell-like properties and tumorigenic capabilities, having the abilities of self-renewal and differentiation, thereby being able to generate heterogeneous lineages of cancer cells and lead to resistance toward anti-tumor treatments. Highly resistant to conventional chemo- and radiotherapy, CSCs have heterogeneity and can migrate to different organs and metastasize. Recent studies have demonstrated that the population of CSCs and the progression of cancer are increased by the deregulation of different epigenetic pathways having effects on gene expression patterns and key pathways connected with cell proliferation and survival. Further, epigenetic modifications (DNA methylation, histone modifications, and RNA methylations) have been revealed to be key drivers in the formation and maintenance of CSCs. Hence, identifying CSCs and targeting epigenetic pathways therein can offer new insights into the treatment of cancer. In the present review, recent studies are addressed in terms of the characteristics of CSCs, the resistance thereof, and the factors influencing the development thereof, with an emphasis on different types of epigenetic changes in genes and main signaling pathways involved therein. Finally, targeted therapy for CSCs by epigenetic drugs is referred to, which is a new approach in overcoming resistance and recurrence of cancer.

Keywords: Cancer stem cell (CSC); Drug resistance; Epi-drugs; Epigenetic modifications; Signaling pathway.

Fig. 1

Proposed models for cancer stem cells (CSCs) origin in cancer development. In the normal differentiation process, a cell differentiates to form two cells, differentiated and primitive. A finally differentiated cell is formed from precursor progenitor cell and eventually subject to apoptosis. CSC may originate from a normal stem cell, a normal progenitor cell, or a normal differentiated cell by genetic mutation which will activate self-renewal genes in them. Also cancer cells via EMT can change to CSCs

Fig. 2

Schematic representation of the cancer stem cell microenvironment or niche. Progression of tumor needs a cooperative interplay between CSCs and their niche. The CSC niche made of various cells including mesenchymal stem cells (MSCs), endothelial cells, cancer-associated fibroblasts (CAFs) and immune cells, tumor-associated macrophages (TAMs), regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), T cells and B cells. These cells secrete various growth factors and cytokines which promote tumorigenesis, tumor progression, and immunosuppression

Fig. 3

Schematic illustration of factors related to raising resistance in CSCs. Activation of quiescence, cell survival pathways, enhanced drug efflux, the apoptotic signaling disability, enhanced DNA damage repair, enhanced detoxifying activity, and enhanced scavenging of free radicals are feasible agents lead to the CSCs resistance

Fig. 4

Graphical representation of CSCs epigenetic regulation. Histone modifications, DNA methylation, RNA methylartion and noncoding RNA molecules (lncRNAs and miRNAs) play important role in CSC biology and plasticity. a lncRNAs interplay between the various layers of epigenetic gene regulation such as histone modifiers or serving as ceRNAs for miRNAs; while miRNAs can act as anti- or pro-CSC regulators. b Histone-modifying enzymes act between CSCs and their non-CSC counterparts, such as HAT, EZH2, and HDAC. c The DNMT1 methyltransferase methylates CpG sites relate to methylation of genes vital for stemness feature, differentiation and quienscent of CSCs. d RNA methylation increase self-renewal of CSCs

Fig. 5

The main CSCs signaling pathways regulation by epigenetic mechanisms. Epigenetic deregulation of CSC-related signaling pathways enables cancer cells to obtain self-renewal properties and drug resistance characteristics. Hedgehog signaling pathway can be activated by Shh promoter hypomethylation and enhance HDAC1 expression. Wnt/β-catenin signaling can be strengthened by reduced DKK1 inhibitor expression of it via promoter hypermethylation and enhanced H3K27me3 and reduced acetylation at H3K16. Notch signaling focus on genes including Hes1 and Hes5 which can be active by STRAP at their promoter region

Fig. 6

BMP, TGF-β and the FGF pathways in CSCs. BMP signaling is involved in CSC differentiation. The TGF-β/ Activin/Nodal pathway has different function in CSCs according to cancer type such as CSC self-renewal. TGF-β and the FGF pathways have role in pluripotency of CSCs

Fig. 7

Schematic representation of CSCs epigenome as a target for cancer treatment. Various drugs including Aza-dC (Decitabine), SGI-110 or Zebularine, can reduce DNMT1 protein levels and global methylation. HDAC inhibitors (HDACI), including Mocetinostat, Entinostat and Belinostat, have demonstrated good effect toward inhibitation of HDAC. lncRNAs can be inhibit by GapmeRs or small molecule inhibitors which eventually will be disrupt