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Epithelial-mesenchymal transition (EMT) is an important process triggered during cancer metastasis. Regulation of EMT is mostly initiated by outside signalling, including TGF-β, growth factors, Notch ligand, Wnt, and hypoxia. Many signalling pathways have been delineated to explain the molecular mechanisms of EMT. In this review, we will focus on the epigenetic regulation of two critical EMT signalling pathways: hypoxia and TGF-β. For hypoxia, hypoxia-induced EMT is mediated by the interplay between chromatin modifiers histone deacetylase 3 (HDAC3) and WDR5 coupled with the presence of histone 3 lysine 4 acetylation (H3K4Ac) mark that labels the promoter regions of various traditional EMT marker genes (e.g. CDH1 , VIM ). Recently identified new hypoxia-induced EMT markers belong to transcription factors (e.g. SMO, GLI1) that mediate EMT themselves. For TGF-β-induced ΕΜΤ, global chromatin changes, removal of a histone variant (H2A.Z), and new chromatin modifiers (e.g. UTX, Rad21, PRMT5, RbBP5, etc) are identified to be crucial for the regulation of both EMT transcription factors (EMT-TFs) and EMT markers (EMT-Ms). The epigenetic mechanisms utilized in these two pathways may serve as good model systems for other signalling pathways and also provide new potential therapeutic targets.

Cancer stemness represents one of the major mechanisms that predispose patients to tumor aggressiveness, metastasis, and treatment resistance. MicroRNA biogenesis is an important process controlling miRNA processing and maturation. Deregulation of miRNA biogenesis can lead to tumorigenesis and cancer stemness. DDX17 is a co-factor of the miRNA microprocessor. Misregulation of DDX17 can be associated with cancer stemness. K63-linked polyubiquitination of DDX17 presents a concerted mechanism of decreased synthesis of stemness-inhibiting miRNAs and increased transcriptional activation of stemness-related gene expression. K63-linked polyubiquitination of HAUSP serves as a scaffold to anchor HIF-1α, CBP, the mediator complex, and the super-elongation complex to enhance HIF-1α-induced gene transcription. Recent progress in RNA modifications shows that RNA N6-methyladenosine (m6A) modification is a crucial mechanism to regulate RNA levels. M6A modification of miRNAs can also be linked to tumorigenesis and cancer stemness. Overall, miRNA biogenesis and K63-linked polyubiquitination of DDX17 play an important role in the induction of cancer stemness. Delineation of the mechanisms and identification of suitable targets may provide new therapeutic options for treatment-resistant cancers.

Ubiquitination modulates a large repertoire of cellular functions and thus, dysregulation of the ubiquitin system results in multiple human diseases, including cancer. Ubiquitination requires an E3 ligase, which is responsible for substrate recognition and conferring specificity to ubiquitination. HUWE1 is a multifaceted HECT domain-containing ubiquitin E3 ligase, which catalyzes both mono-ubiquitination and K6-, K48- and K63-linked poly-ubiquitination of its substrates. Many of the substrates of HUWE1 play a crucial role in maintaining the homeostasis of cellular development. Not surprisingly, dysregulation of HUWE1 is associated with tumorigenesis and metastasis. HUWE1 is frequently overexpressed in solid tumors, but can be downregulated in brain tumors, suggesting that HUWE1 may possess differing cell-specific functions depending on the downstream targets of HUWE1. This review introduces some important discoveries of the HUWE1 substrates, including those controlling proliferation and differentiation, apoptosis, DNA repair, and responses to stress. In addition, we review the signaling pathways HUWE1 participates in and obstacles to the identification of HUWE1 substrates. We also discuss up-to-date potential therapeutic designs using small molecules or ubiquitin variants (UbV) against the HUWE1 activity. These molecular advances provide a translational platform for future bench-to-bed studies. HUWE1 is a critical ubiquitination modulator during the tumor progression and may serve as a possible therapeutic target for cancer treatment.

Hypoxia is an important microenvironmental factor that induces cancer metastasis. Hypoxia/hypoxia-inducible factor-1α (HIF-1α) regulates many important steps of the metastatic processes, especially epithelial-mesenchymal transition (EMT) that is one of the crucial mechanisms to cause early stage of tumor metastasis. To have a better understanding of the mechanism of hypoxia-regulated metastasis, various hypoxia/HIF-1α-regulated target genes are categorized into different classes including transcription factors, histone modifiers, enzymes, receptors, kinases, small GTPases, transporters, adhesion molecules, surface molecules, membrane proteins, and microRNAs. Different roles of these target genes are described with regards to their relationship to hypoxia-induced metastasis. We hope that this review will provide a framework for further exploration of hypoxia/HIF-1α-regulated target genes and a comprehensive view of the metastatic picture induced by hypoxia.

Background DNA N6-methyldeoxyadenosine (6mA) is rarely present in mammalian cells and its nuclear role remains elusive. Results Here we show that hypoxia induces nuclear 6mA modification through a DNA methyltransferase, METTL4, in hypoxia-induced epithelial-mesenchymal transition (EMT) and tumor metastasis. Co-expression of METTL4 and 6mA represents a prognosis marker for upper tract urothelial cancer patients. By RNA sequencing and 6mA chromatin immunoprecipitation-exonuclease digestion followed by sequencing, we identify lncRNA RP11-390F4.3 and one novel HIF-1α co-activator, ZMIZ1, that are co-regulated by hypoxia and METTL4. Other genes involved in hypoxia-mediated phenotypes are also regulated by 6mA modification. Quantitative chromatin isolation by RNA purification assay shows the occupancy of lncRNA RP11-390F4.3 on the promoters of multiple EMT regulators, indicating lncRNA-chromatin interaction. Knockdown of lncRNA RP11-390F4.3 abolishes METTL4-mediated tumor metastasis. We demonstrate that ZMIZ1 is an essential co-activator of HIF-1α. Conclusions We show that hypoxia results in enriched 6mA levels in mammalian tumor cells through METTL4. This METTL4-mediated nuclear 6mA deposition induces tumor metastasis through activating multiple metastasis-inducing genes. METTL4 is characterized as a potential therapeutic target in hypoxic tumors.

Intratumoural hypoxia induces HIF-1α and promotes tumour progression, metastasis and treatment resistance. HIF-1α stability is regulated by VHL-E3 ligase-mediated ubiquitin-dependent degradation; however, the hypoxia-regulated deubiquitinase that stabilizes HIF-1α has not been identified. Here we report that HAUSP (USP7) deubiquitinase deubiquitinates HIF-1α to increase its stability, induce epithelial-mesenchymal transition and promote metastasis. Hypoxia induces K63-linked polyubiquitinated HAUSP at lysine 443 to enhance its functions. Knockdown of HAUSP decreases acetylation of histone 3 lysine 56 (H3K56Ac). K63-polyubiquitinated HAUSP interacts with a ubiquitin receptor CBP to specifically mediate H3K56 acetylation. ChIP-seq analysis of HAUSP and HIF-1α binding reveals two motifs responsive to hypoxia. HectH9 is the E3 ligase for HAUSP and a prognostic marker together with HIF-1α. This report demonstrates that hypoxia-induced K63-polyubiquitinated HAUSP deubiquitinates HIF-1α and causes CBP-mediated H3K56 acetylation on HIF-1α target gene promoters to promote EMT/metastasis, further defining HAUSP as a therapeutic target in hypoxia-induced tumour progression. Hypoxia-induced transcriptional responses mediated by HIF-1a are regulated through the ubiquitin-dependent pathway to control HIF-1a stability. Here the authors show that the deubiquitinase HAUSP modulates the stability of HIF-1a and K63-polyubiquitinated HAUSP serves as an anchor for HIF-1a-induced gene transcription.

USP7, one of the most abundant ubiquitin-specific proteases (USP), plays multifaceted roles in many cellular events, including oncogenic pathways. Accumulated studies have suggested that USP7, through modulating the MDM2/MDMX-p53 pathway, is a promising target for cancer treatment; however, little is known about the function of USP7 in p53-deficient tumors. Here we report that USP7 regulates the autoregulation of SMAD3, a key regulator of transforming growth factor β (TGFβ) signaling, that represses the cell progression of p53-deficient lung cancer. CRISPR/Cas9-mediated inactivation of USP7 in p53-deficient lung cancer H1299 line resulted in advanced cell proliferation in vitro and in xenograft tumor in vivo. Genome-wide analyses (ChIP-seq and RNA-seq) of USP7 KO H1299 cells reveal a dramatic reduction of SMAD3 autoregulation, including decreased gene expression and blunted function of associated super-enhancer (SE). Furthermore, biochemical assays show that SMAD3 is conjugated by mono-ubiquitin, which negatively regulates the DNA-binding function of SMAD3, in USP7 KO cells. In addition, cell-free and cell-based analyses further demonstrate that the deubiquitinase activity of USP7 mediates the removal of mono-ubiquitin from SMAD3 and facilitates the DNA-binding of SMAD3-SMAD4 dimer at SMAD3 locus, and thus enhance the autoregulation of SMAD3 . Collectively, our study identified a novel mechanism by which USP7, through catalyzing the SMAD3 de-monoubiquitination, facilitates the positive autoregulation of SMAD3 , and represses the cancer progression of p53-deficient lung cancer.

Asymmetric cell division (ACD) plays a pivotal role in development, tissue homeostasis, and stem cell maintenance. Emerging evidence suggests that long non-coding RNAs (lncRNAs) are key regulators of ACD, orchestrating the intricate molecular machinery that governs cell fate determination. This review summarizes current literature to elucidate the diverse roles of lncRNAs in modulating ACD across various biological contexts. The regulatory mechanisms of asymmetric cell division mediated by lncRNAs, including their interactions with protein effectors, epigenetic regulation, and subcellular localization are explored. Additionally, we discuss the implications of dysregulated lncRNAs in mediating ACD that lead to tumorigenesis. By integrating findings from diverse experimental models and cell types, this review provides insights into the multifaceted roles of lncRNAs in governing asymmetric cell division, shedding light on fundamental biological processes. Further research in this area may lead to the development of novel therapies targeting dysregulated lncRNAs to restore proper cell division and function. The knowledge of lncRNAs regulating ACD could potentially revolutionize the field of regenerative medicine and cancer therapy by targeting specific lncRNAs involved in ACD. By unraveling the complex interactions between lncRNAs and cellular processes, the potential novel opportunities for precision medicine approaches may be uncovered.

The transcription factor Twist1 interacts with the Bmi1 polycomb group protein. This complex is proposed to regulate the epithelial–mesenchymal transition and the tumour-initiating capability of head-and-neck squamous cell carcinoma cells. The epithelial–mesenchymal transition (EMT), one of the main mechanisms underlying development of cancer metastasis, induces stem-like properties in epithelial cells. Bmi1 is a polycomb-group protein that maintains self-renewal, and is frequently overexpressed in human cancers. Here, we show the direct regulation of BMI1 by the EMT regulator, Twist1. Furthermore, Twist1 and Bmi1 were mutually essential to promote EMT and tumour-initiating capability. Twist1 and Bmi1 act cooperatively to repress expression of both E-cadherin and p16INK4a. In patients with head and neck cancers, increased levels of both Twist1 and Bmi1 correlated with downregulation of E-cadherin and p16INK4a, and was associated with the worst prognosis. These results suggest that Twist1-induced EMT and tumour-initiating capability in cancer cells occurs through chromatin remodelling, which leads to unfavourable clinical outcomes.

Epithelial–mesenchymal transition (EMT), which is characterized by the suppression of the adhesion protein E-cadherin, is a crucial process that promotes metastasis and stem-like properties of cancer cells. However, the dissociation of cellular aggregates is not sufficient to explain why cancer cells move, and the motile nature of cancer cells undergoing EMT remains elusive. Here, we identify a mechanism in which the EMT inducer Twist1 elicits cancer cell movement through activation of RAC1. Twist1 cooperates with BMI1 to suppress let-7i expression, which results in upregulation of NEDD9 and DOCK3, leading to RAC1 activation and enabling mesenchymal-mode movement in three-dimensional environments. Moreover, the suppression of let-7i contributes to Twist1-induced stem-like properties. Clinically, activation of the Twist1– let-7i –NEDD9 axis in head and neck cancer patients correlates with tumour invasiveness and worse outcome. Our results uncover an essential mechanism to explain how Twist1 induces the motile stem-like cancer cell phenotype beyond simply suppressing E-cadherin. Yang and colleagues delineate a pathway that controls cell migration in 3D environments following Twist1-mediated epithelial-to-mesenchymal transition. They show that Twist1 represses the let-7i microRNA, leading to upregulation of the RAC1-activating factors NEDD9 and DOCK3, and inducing mesenchymal-mode motility and tumour invasion in vivo .