Targeting Epigenetic Modifiers of Tumor Plasticity and Cancer Stem Cell Behavior

Abstract

Tumor heterogeneity poses one of the greatest challenges to a successful treatment of cancer. Tumor cell populations consist of different subpopulations that have distinct phenotypic and genotypic profiles. Such variability poses a challenge in successfully targeting all tumor subpopulations at the same time. Relapse after treatment has been previously explained using the cancer stem cell model and the clonal evolution model. Cancer stem cells are an important subpopulation of tumor cells that regulate tumor plasticity and determine therapeutic resistance. Tumor plasticity is controlled by genetic and epigenetic changes of crucial genes involved in cancer cell survival, growth and metastasis. Targeting epigenetic modulators associated with cancer stem cell survival can unlock a promising therapeutic approach in completely eradicating cancer. Here, we review various factors governing epigenetic dysregulation of cancer stem cells ranging from the role of epigenetic mediators such as histone and DNA methyltransferases, histone deacetylases, histone methyltransferases to various signaling pathways associated with cancer stem cell regulation. We also discuss current treatment regimens targeting these factors and other promising inhibitors in clinical trials.

Keywords: cancer stem cells; epigenetics; inhibitors; signaling; tumoral plasticity.

Figure 1

Conceptual diagram describing intertumoral heterogeneity and intratumoral heterogeneity. Created with BioRender.com (accessed date on 28 March 2022).

Figure 2

Schematic describing the two current models of cancer stem cells. Tumor heterogeneity is produced by clonal evolution and differentiation of CSCs into CSC and non-CSC tumor cells in the Hierarchical model while in the Stochastic model it is caused by the extended accumulation of genetic mutations in tumor cells. Created with BioRender.com.

Figure 3

Conceptual diagram describing key epigenetic modifiers, their mode of action and their select inhibitors. Histone writers add methyl groups (Me3) or acetyl groups (Ac) can be inhibited by approved drug tazemetostat. DNA writers, such as DMT (DNA methyltransferases) remove methyl groups (Me3) and can be inhibited by approved drugs; azacitidine and decitabine. Histone erasers such as HDAC (histone deacetylases) remove acetyl groups (Ac) and can be inhibited by approved drugs; vorinostat, panobinostat, belinostat and romidepsin, while DNA erasers such as TET (ten-eleven translocation) oxidize 5-methyl cytosine into 5 hydroxymethyl cytosine. Histone readers such as the BET proteins can recognize acetylated lysine residues on histone tails, and they can be inhibited by BMS-986158 and ZEN003694. Created with BioRender.com.