In addition, lincRNA regulator of reprogramming (ROR) negatively regulates miR-34a expression by inhibiting histone H3 acetylation in the promoter, leading to the reversal of gemcitabine-induced autophagy and apoptosis in breast cancer (Chen Y.M. updated overview of CSCs. We then focus on microRNA-34a (miR-34a), a tumor-suppressive microRNA (miRNA) devoid in many CSCs and advanced tumors. Being a member of the miR-34 family, miR-34a was identified as a p53 target in 2007. It is a bona fide tumor suppressor, and its expression is dysregulated and downregulated in various human cancers. By targeting stemness factors such as NOTCH, MYC, BCL-2, and CD44, miR-34a epigenetically and negatively regulates the functional properties of CSCs. We shall briefly discuss potential reasons behind the failure of the first-in-class clinical trial of MRX34, a liposomal miR-34a mimic. Finally, we offer several clinical settings where miR-34a can potentially be deployed to Mesaconitine therapeutically target CSCs and advanced, therapy-resistant, and p53-mutant tumors in order to overcome therapy Rabbit polyclonal to MEK3 resistance and curb tumor relapse. by negatively regulating PCSCs (Liu et al., 2011). Below, we further discuss the role of miR-34a in regulating CSCs in a spectrum of cancers, especially with respect to regulating the factors involved in tumor microenvironment (TME), tumor immune microenvironment (TiME), metabolism, and EMT. We shall also discuss the recent advances in translational research of miR-34a and offer several clinical settings where miR-34a could be deployed to therapeutically target CSCs for tackling therapy resistance and tumor relapse. Regulation of miR-34a Expression In addition to p53-regulated expression, miR-34a can also be regulated in a p53-independent manner (Figure 1C). Indeed, miR-34a has been shown to be transcriptionally regulated via TP63, TP73, and other transcription factors (TFs) such as STAT3, MYC, and EMT-TFs, as well as posttranscriptionally regulated by various long non-coding RNAs (lncRNAs) (Slabkov et al., 2017; Figure 1C). In addition, miR-34a expression can be context dependent and may dynamically change during EMT, hypoxia, and inflammation (Siemens et al., 2011; Yang et al., 2012; Li H. et al., 2017). miR-34a expression is also regulated through epigenetic regulation. For example, enhancer of zeste homolog 2 [EZH2; a histone 3 lysine 27 (H3K27) methyltransferase], in conjunction with HOTAIR, has been shown to silence miR-34a by induction of heterochromatin Mesaconitine (Li C.H. et al., 2017). Moreover, Sirt7, a NAD+-dependent class III histone deacetylase, binds to the promoter of miR-34a and deacetylates the H3K18ac, thus repressing miR-34a expression (Zhang et al., 2015). Many lncRNAs also epigenetically regulate miR-34a expression (Figure 1C). For example, the lncRNA HOTAIR represses miR-34a by enhancing DNA methylation of the promoter via recruiting and binding to polycomb repressive complex 2 (PRC2), which promotes tumor metastasis by controlling EMT-related genes (Liu et al., 2015). In addition, lincRNA regulator of reprogramming (ROR) negatively regulates miR-34a expression by inhibiting histone H3 acetylation in the promoter, leading to the reversal of gemcitabine-induced autophagy and apoptosis in breast cancer (Chen Y.M. et al., 2016). The lncRNA myocardial infarction associated transcript (MIAT) can interact with DNMT3a and epigenetically silence miR-34a expression by hypermethylating the promoter (Fu et al., 2018). Interestingly, a novel lncRNA, Lnc34a, has been reported to recruit Dnmt3a via PHB2 and HDAC1 to methylate and deacetylate the promoter simultaneously, hence Mesaconitine epigenetically silencing miR-34a expression independently of p53 (Wang et al., 2016). Lnc34a promotes CSC self-renewal, and Lnc34a asymmetry leads to cell fate asymmetry in CSC division by directly targeting miR-34a to cause its spatial imbalance (Wang et al., 2016). Moreover, Lnc34a may promote bone metastasis through suppressing miR-34a, which leads to inhibition of Smad4 and alterations of transcription of the downstream genes [i.e., connective tissue growth factor (CTGF) and interleukin (IL)-11] that are associated with bone metastasis (Zhang et al., 2019). An Evolving View of the CSC Concept Heterogeneity is an omnipresent feature of cancer cells and genomic region (Figure 1C), and miR-34a, in turn, targets E2F3 during granulopoiesis (Pulikkan et al., 2010). miR-34a overexpression resulted in granulocytic differentiation of AML blast cells as assessed morphologically and by increased expression of myeloid markers, such as CD11b.