Transcriptional regulation of cancer stem cell: regulatory factors elucidation and cancer treatment strategies

Abstract

Cancer stem cells (CSCs) were first discovered in the 1990s, revealing the mysteries of cancer origin, migration, recurrence and drug-resistance from a new perspective. The expression of pluripotent genes and complex signal regulatory networks are significant features of CSC, also act as core factors to affect the characteristics of CSC. Transcription is a necessary link to regulate the phenotype and potential of CSC, involving chromatin environment, nucleosome occupancy, histone modification, transcription factor (TF) availability and cis-regulatory elements, which suffer from ambient pressure. Especially, the expression and activity of pluripotent TFs are deeply affected by both internal and external factors, which is the foundation of CSC transcriptional regulation in the current research framework. Growing evidence indicates that regulating epigenetic modifications to alter cancer stemness is effective, and some special promoters and enhancers can serve as targets to influence the properties of CSC. Clarifying the factors that regulate CSC transcription will assist us directly target key stem genes and TFs, or hinder CSC transcription through environmental and other related factors, in order to achieve the goal of inhibiting CSC and tumors. This paper comprehensively reviews the traditional aspects of transcriptional regulation, and explores the progress and insights of the impact on CSC transcription and status through tumor microenvironment (TME), hypoxia, metabolism and new meaningful regulatory factors in conjunction with the latest research. Finally, we present opinions on omnidirectional targeting CSCs transcription to eliminate CSCs and address tumor resistance.

Keywords: CSC; DNA elements; Signaling pathways,epigenetics; TF; TME; Transcription regulation.

Fig. 1

Targeting TFs in CSC from multiple perspectives A Directly blocking the combination of TFs and DNA: mainly through epigenetic mechanisms. B Targeting TFs mRNA to regulate the level: miRNAs target the inactivation of TF mRNA, and TFs mediate miRNA transcription. LncRNA influences TF mRNA through miRNA and forms ceRNA with miRNA. CircRNA targets TF mRNA through miRNA. RBP binds TF mRNA to affect the stability and translation. The modification of TF mRNA may play a role. C Promoting TFs degradation by ubiquitination. D Modulating various signaling pathways to affect TFs transcription and activity by diverse agents: it is effective for the TFs to regulate transcription of CSC by acting on ligands, receptors, complexes, and other TFs of various signaling pathways. E Inhibiting cell markers that regulate TFs gene expression. F Inducing ambient pressure such as metabolism, hypoxia and immune response to cause TFs inactivation

Fig. 2

Multiple mechanisms of environmental stress regulating CSC transcription A The immune cells in TME activate the STAT, Wnt, AKT and Notch pathway of CSC by mainly releasing cytokines (IL-6) and inducing contact. CAFs secrete various substances (cytokines, POSTN, miRNA) to stimulate distinct pathways of CSC (Wnt/β-Catenin, PI3K/AKT/mTOR, STAT). ECM exerts effect on the PI3K and Hh pathways, as well as transcription of pluripotent TFs through mechanical stress and CSC markers (CD44). B Hypoxia causes the production of HIF and ROS. HIF-1 secretes miRNAs and activates the Wnt, Notch, PI3K/mTOR pathways, as well as acts on histone modifications. HIF-2 tends to directly regulate the gene expression of various TFs. Hypoxia induced ROS may support a transcription promoting role of CSCs. C OXPHOS occurring in the mitochondria of CSC can indirectly affect (through the release of ROS) or directly bear on the expression and effect of TFs. The alterations of mitochondrial function and state (mitochondrial fission and mitophagy) regulate the expression of TFs. The key enzymes in the CSC glycolysis process act on TF through the Hippo pathway and cell marker (CD133). Lactate metabolism plays a role in histone modification (lactylation) of CSC and ubiquitination of TF proteins. Lipid metabolism (LDs and FAO) is associated with the Wnt, Notch, Hippo, Hh and PI3K/AKT pathways and makes a difference in histone modifications (acetylation). Gln deprivation promotes pluripotent gene silencing and increases histone trimethylation

Fig. 3

Regulating various aspects of CSC transcription from distinct perspectives The transcription of CSC involves TFs, epigenetic modification and cis-regulatory elements. Signal pathways, TME, hypoxia stress, metabolic stimulation, cell surface markers, DNA damage and circadian rhythm affect at least one of the three links to alter the phenotype and behavior of CSC