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Recently, super-enhancers (SEs) have been identified as a unique type of transcriptional regulation involved in cancer development. SEs exhibit a size, high transcription factor density, and strong binding to the transcriptional machinery compared with typical enhancers. SEs play an essential role in cell growth, differentiation, and disease initiation and progression including tumorigenesis. In particular, cancer-specific SEs have been proven to be key oncogenic drivers types of tumor cells. Furthermore, it has been confirmed that cancer-specific SEs can mediate the dysregulation of signaling pathways and promote cancer cell growth. Additionally, therapeutic strategies directly targeting SE components, for example, by disrupting SE structure or inhibiting SE cofactors, have shown a good curative effect on various cancers.

Super-enhancers (SEs) consist of a cluster of many enhancers bound to a great number of transcription factors. They are critical cis-regulatory elements that determine the identity of various human cell types. During tumorigenesis, DNA mutations and indels, chromosomal rearrangements, three-dimensional chromatin structural changes, and viral infections mediate oncogenic SE activation, and activated SEs have been found to regulate the expression of oncogenic genes. Inhibition specifically targeted to oncogenic SE assembly and activation provides a novel powerful therapeutic strategy for various cancers. In this paper, we first introduce the current understanding of oncogenic SE assembly and activation and then summarize the pathogenic factors and mechanism of oncogenic SE activation. Next, we elaborate on the oncogenic functions of SEs in cancers and the application of SEs as therapeutic targets. Finally, we turn our focus to the use of SEs in basic research and clinical trials.Cancer: Enhancing the expression of cancer-causing genesDrugs that block the assembly and activation of large DNA segments involved in enhancing gene expression could help in the treatment of cancer. Faqing Tang of Hunan Cancer Hospital in Changsha, China, and colleagues review the ways in which cancer cells hijack clusters of gene-regulating sequences known as super-enhancers, regulatory gene regions that normally help determine a cell’s unique identity, to drive the aberrant gene activity that fuels tumor growth. The researchers describe how numerous factors, ranging from internal DNA alterations, both large and small, to viral infections and other external assaults, can spur the formation of cancer-causing super-enhancers, leading to out-of-control gene expression. Therapies that selectively target these super-enhancers are now in early clinical testing. However, more studies of super-enhancers and their role in cancer development are needed to inform future drug development.

Cancer remains a significant global health burden due to its high morbidity and mortality. Oncogene-targeted therapy and immunotherapy have markedly improved the 5-year survival rate in the patients with advanced or metastatic tumors compared to outcomes in the era of chemotherapy/radiation. Nevertheless, the majority of patients remain incurable. Initial therapies eliminate the bulk of tumor cells, yet residual populations termed drug-tolerant persister cells (DTPs) survive, regenerate tumor and even drive distant metastases. Notably, DTPs frequently render tumor cross-resistance, a detrimental phenomenon observed in the patients with suboptimal responses to subsequent therapies. Analogous to species evolution, DTPs emerge as adaptative products at the cellular level, instigated by integrated intracellular stress responses to therapeutic pressures. These cells exhibit profound heterogeneity and adaptability shaped by the intricate feedforward loops among tumor cells, surrounding microenvironments and host ecology, which vary across tumor types and therapeutic regimens. In this review, we revisit the concept of DTPs, with a focus on their generation process upon targeted therapy or immunotherapy. We dissect the critical phenotypes and molecule mechanisms underlying DTPs to therapy from multiple aspects, including intracellular events, intercellular crosstalk and the distant ecologic pre-metastatic niches. We further spotlight therapeutic strategies to target DTP vulnerabilities, including synthetic lethality approaches, adaptive dosing regimens informed by mathematical modeling, and immune-mediated eradication. Additionally, we highlight synergistic interventions such as lifestyle modifications (e.g., exercise, stress reduction) to suppress pro-tumorigenic inflammation. By integrating mechanistic insights with translational perspectives, this work bridges the gap between DTP biology and clinical strategies, aiming for optimal efficacy and preventing relapse.

seRNA is a noncoding RNA (ncRNA) transcribed from active super-enhancer (SE), through which SE exerts biological functions and participates in various physiological and pathological processes. seRNA recruits cofactor, RNA polymerase II and mediator to constitute and stabilize chromatin loop SE and promoter region, which regulates target genes transcription. In tumorigenesis, DNA insertion, deletion, translocation, focal amplification and carcinogen factor mediate oncogenic SE generation, meanwhile, oncogenic SE transcribes into tumor-related seRNA, termed as oncogenic seRNA. Oncogenic seRNA participates in tumorigenesis through activating various signal-pathways. The recent reports showed that oncogenic seRNA implicates in a widespread range of cytopathological processes in cancer progression including cell proliferation, apoptosis, autophagy, epithelial-mesenchymal transition, extracellular matrix stiffness and angiogenesis. In this article, we comprehensively summarized seRNA’s characteristics and functions, and emphatically introduced inducible formation of oncogenic seRNA and its functional mechanisms. Lastly, some research strategies on oncogenic seRNA were introduced, and the perspectives on cancer therapy that targets oncogenic seRNA were also discussed.

Circular RNAs (circRNAs) are a novel type of endogenous non-coding RNAs, which are covalently closed loop structures formed by precursor mRNAs (pre-mRNAs) through back-splicing. CircRNAs are abnormally expressed in many tumors, and play critical roles in a variety of tumors as oncogenes or tumor suppressor genes by sponging miRNAs, regulating alternative splicing and transcription, cis-regulating host genes, interacting with RNA binding proteins (RBPs) or encoding polypeptides. Among them, the regulation of circRNAs on their corresponding host genes is a critical way for circRNAs to exit their functions. Accumulating evidence suggests that circRNAs are able to regulate the expression of host genes at the transcriptional level, post-transcriptional level, translational level, post-translational level, or by encoding polypeptides. Therefore, this paper mainly summarized the roles and association of circRNAs and their corresponding host genes in tumorigenesis and tumor progression, generalized the circRNAs that function synergistically or antagonistically with their host genes, and elaborated the mechanisms of mutual regulation between circRNAs and their host genes. More importantly, this review provides specific references for revealing the potential application of circRNAs combined with their host genes in tumor diagnosis, treatment and prognosis.

Nasopharyngeal carcinoma (NPC) is a common malignant cancer in southern China that has highly invasive and metastatic features and causes high mortality, but the underlying mechanisms of this malignancy remain unclear. In this study, we utilized ChIP-Seq to identify metastasis-specific super enhancers (SEs) and found that the SE of LOC100506178 existed only in metastatic NPC cells and powerfully aggravated NPC metastasis. This metastatic SE transcribed into lncRNA LOC100506178, and it was verified as a seRNA through GRO-Seq. Furthermore, SE-derived seRNA LOC100506178 was found to be highly expressed in metastatic NPC cells and NPC lymph node metastatic tissues. Knockdown of seRNA LOC100506178 arrested the invasion and metastasis of NPC cells in vitro and in vivo, demonstrating that seRNA LOC100506178 accelerates the acquisition of NPC malignant phenotype. Mechanistic studies revealed that seRNA LOC100506178 specifically interacted with the transcription factor hnRNPK and modulated the expression of hnRNPK. Further, hnRNPK in combination with the promoter region of MICAL2 increased Mical2 transcription. Knockdown of seRNA LOC100506178 or hnRNPK markedly repressed MICAL2, Vimentin and Snail expression and upregulated E-cadherin expression. Overexpression of seRNA LOC100506178 or hnRNPK markedly increased MICAL2, Vimentin and Snail expression and decreased E-cadherin expression. Therefore, seRNA LOC100506178 may promote MICAL2 expression by upregulating hnRNPK, subsequently enhancing EMT process and accelerating the invasion and metastasis of NPC cells. seRNA LOC100506178 has the potential to serve as a novel prognostic biomarker and therapeutic target in NPC patients.

NOP2/Sun RNA methyltransferase 2 (NSUN2), an important methyltransferase of m5C, has been poorly studied in cancers, and the relationship between NSUN2 and immunity remains largely unclear. Therefore, the purpose of this study was to explore the expression and prognostic value of NSUN2 and the role of NSUN2 in immunity in cancers. The TIMER, CPTAC and other databases were used to analyze the expression of NSUN2, its correlation with clinical stage and its prognostic value across cancers. Moreover, the TISIDB, TIMER2.0 and Sangerbox platform were used to depict the relationships between NSUN2 and immune molecular subtypes, tumor-infiltrating lymphocytes (TILs), immune checkpoints (ICPs) and immunoregulatory genes. Furthermore, the NSUN2-interacting proteins and related genes as well as the coexpression networks of NSUN2 in LIHC, LUAD and HNSC were explored with the STRING, DAVID, GEPIA2 and LinkedOmics databases. Finally, the subcellular location and function of NSUN2 in HepG2, A549 and 5-8F cells were investigated by performing immunofluorescence, CCK-8 and wound healing assays. Overall, NSUN2 was highly expressed and related to a poor prognosis in most types of cancers and was also significantly associated with immune molecular subtypes in some cancer types. Furthermore, NSUN2 was significantly associated with the levels of ICPs and immunoregulatory genes. In addition, NSUN2 was found to be involved in a series of immune-related biological processes, such as the humoral immune response in LIHC and LUAD and T-cell activation and B-cell activation in HNSC. Immunofluorescence and CCK-8 assays also confirmed that NSUN2 was widely expressed in the nucleus and cytoplasm, and overexpression of NSUN2 promoted the proliferation and migration of HepG2, A549 and 5-8F cells. NSUN2 was also confirmed to positively regulate the expression of PD-L1. NSUN2 serves as a pan-cancer prognostic biomarker and is correlated with the immune infiltration of tumors.

Nucleic acid aptamers are a class of high-affinity nucleic acid ligands. They serve as “chemical antibodies” since their high affinity and specificity. Nucleic acid aptamers are generated from nucleic acid random-sequence using a systematic evolution of ligands by exponential enrichment (SELEX) technology. SELEX is a process of effectively selecting aptamers from different targets. A newly developed cell-based SELEX technique has been widely used in biomarker discovery, early diagnosis and targeted cancer therapy, particular at colorectal cancer (CRC). Combined with nanostructures, nano-aptamer-drug delivery system was constructed for drug delivery. Various nanostructures functionalized with aptamers are highly efficient and has been used in CRC therapeutic applications. In the present, we introduce a cell- SELEX technique, and summarize the potential application of aptamers as biomarkers in CRC diagnosis and therapy. And some characteristics of aptamer-targeted nanocarriers in CRC have been expatiated. The challenges and perspectives for cell-SELEX are also discussed.

Leukemia immunotherapy has been dominant via using synthetic antibodies to target cluster of differentiation (CD) molecules, nevertheless inevitable cytotoxicity and immunogenicity would limit its development. Recently, increasing reports have focused on nucleic acid aptamers, a class of high-affinity nucleic acid ligands. Aptamers purportedly serve as \"chemical antibodies\", have negligible cytotoxicity and low immunogenicity, and would be widely applied for the therapy and diagnosis of various diseases, especially leukemia. In the preclinical applications, nucleic acid aptamers have displayed the augmented specificity and selectivity via recognizing targets on leukemia cells based on unique three-dimensional conformations. As small molecules with nucleic acid characteristics, aptamers need to be chemically modified to resist nuclease degradation, renal clearance and improve binding affinities. Moreover, aptamers can be linked with neoteric detection techniques to enhance sensitivity and selectivity of diagnosis and therapy. In this review, we summarized aptamers' preparation, chemical modification and conjugation, and discussed the application of aptamers in diagnosis and treatment of leukemia through highly specifically recognizing target molecules. Significantly, the application prospect of aptamers in fusion genes would be introduced.

Nasopharyngeal carcinoma (NPC), primarily found in the southern region of China, is a malignant tumor known for its highly metastatic characteristics. The high mortality rates caused by the distant metastasis and disease recurrence remain unsolved clinical problems. In clinic, the berberine (BBR) compound has widely been in NPC therapy to decrease metastasis and disease recurrence, and BBR was documented as a main component with multiple anti-NPC effects. However, the mechanism by which BBR inhibits the growth and metastasis of nasopharyngeal carcinoma remains elusive. Herein, we show that BBR effectively inhibits the growth, metastasis, and invasion of NPC via inducing a specific super enhancer (SE). From a mechanistic perspective, the RNA sequencing (RNA-seq) results suggest that the RAS–RAF1–MEK1/2–ERK1/2 signaling pathway, activated by the epidermal growth factor receptor (EGFR), plays a significant role in BBR-induced autophagy in NPC. Blockading of autophagy markedly attenuated the effect of BBR-mediated NPC cell growth and metastasis inhibition. Notably, BBR increased the expression of EGFR by transcription, and knockout of EGFR significantly inhibited BBR-induced microtubule associated protein 1 light chain 3 (LC3)-II increase and p62 inhibition, proposing that EGFR plays a pivotal role in BBR-induced autophagy in NPC. Chromatin immunoprecipitation sequencing (ChIP-seq) results found that a specific SE existed only in NPC cells treated with BBR. This SE knockdown markedly repressed the expression of EGFR and phosphorylated EGFR (EGFR-p) and reversed the inhibition of BBR on NPC proliferation, metastasis, and invasion. Furthermore, BBR-specific SE may trigger autophagy by enhancing EGFR gene transcription, thereby upregulating the RAS–RAF1–MEK1/2–ERK1/2 signaling pathway. In addition, in vivo BBR effectively inhibited NPC cells growth and metastasis, following an increase LC3 and EGFR and a decrease p62. Collectively, this study identifies a novel BBR-special SE and established a new epigenetic paradigm, by which BBR regulates autophagy, inhibits proliferation, metastasis, and invasion. It provides a rationale for BBR application as the treatment regime in NPC therapy in future.