Enhancer regulation in cancer: from epigenetics to mA RNA modification.

Enhancers are crucial cis-regulatory DNA elements that regulate gene transcription by interacting with promoters, often over long genomic distances. Unlike promoters, their activity is independent of orientation or proximity to the gene. Active enhancers are transcribed into non-coding enhancer RNAs (eRNAs), which help stabilize enhancer-promoter loops, recruit transcription machinery, and shape the chromatin architecture.

Discovery of potential RAF selective back pocket as a promising biological site for BRAF inhibitors targeting resistant melanoma opens the door for a new generation of kinase inhibitors: Design, synthesis, biological evaluation, and in silico molecular simulation.

Despite the approved combination of BRAF and MEK inhibitors to treat drug-resistant melanoma, serious side effects associated with this combination have been reported, particularly referring to MEK inhibitors. In the current study, an isosteric drug design strategy and were applied leading to the discovery of KS16, a highly potent candidate with a developed pharmacokinetic profile. KS16 exhibited superior efficacy in inhibiting drug-resistant melanoma cell proliferation as a single agent.

Identification of Autophagy-Related Prognostic Signature for Glioblastoma Standard Therapy.

Glioblastoma is an aggressive brain tumor with poor prognosis and survival. Autophagy is induced in tumor cells under stress conditions such as treatment with chemotherapeutic agents and radiotherapy (RT), causing resistance to therapy. Thus, we analyzed autophagy-related genes using public databases to investigate a novel prognostic autophagy signature for glioblastoma patients who received temozolomide (TMZ) and RT.

Vasopressin-Sensitive Aqp2 Regulation Mediated by the TAZ-NR4A1 Axis in Renal Collecting Duct Cells.

Regulation of aquaporin-2 (Aqp2) gene is essential for body water homeostasis. This study investigated how TAZ (a transcriptional coactivator with PDZ-binding motif, Wwtr1) controls vasopressin-driven AQP2 expression. AQP2 expression was studied using collecting duct-specific TAZ-knockout (TAZ; HoxB7Cre) mice and siRNA-mediated knockdown of TAZ in vasopressin-responsive mpkCCDc11 cells.

C24 Ceramide Lipid Nanoparticles for Skin Wound Healing.

: C24 ceramide plays a crucial role in skin regeneration and wound healing; however, its hydrophobic nature limits its application in therapeutic formulations. This study aims to enhance the bioavailability and efficacy of C24 ceramide by developing ceramide-based lipid nanoparticles (C24-LNP) and evaluate their impact on skin regeneration and wound healing. : C24-LNP was synthesized and characterized for aqueous stability and bioavailability.

Experimental Mouse Models and Human Lung Organoid Models for Studying Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality throughout the world, is a highly complicated disease that includes chronic airway inflammation, airway remodeling, emphysema, and mucus hypersecretion. For respiratory function, an intact lung structure is required for efficient air flow through conducting airways and gas exchange in alveoli. Structural changes in small airways and inflammation are major features of COPD.

METTL3-STAT5B interaction facilitates the co-transcriptional mA modification of mRNA to promote breast tumorigenesis.

Enhanced expression of methyltransferase-like 3 (METTL3) promotes the mA modification of specific mRNAs, contributing to breast tumorigenesis. While the mRNA substrates targeted by METTL3 are well characterized, the factors dictating the selection of these specific mRNA remain elusive. This study aimed to examine the regulatory role of the transcription factor STAT5B in METTL3-induced mA modification.

TAZ is involved in breast cancer cell migration via regulating actin dynamics.

Background: Cancer metastasis is dependent on cell migration. Several mechanisms, including epithelial-to-mesenchymal transition (EMT) and actin fiber formation, could be involved in cancer cell migration. As a downstream effector of the Hippo signaling pathway, transcriptional coactivator with PDZ-binding motif (TAZ) is recognized as a key mediator of the metastatic ability of breast cancer cells.

Regulation of mA Methylome in Cancer: Mechanisms, Implications, and Therapeutic Strategies.

Reversible -adenosine methylation of mRNA, referred to as mA modification, has emerged as an important regulator of post-transcriptional RNA processing. Numerous studies have highlighted its crucial role in the pathogenesis of diverse diseases, particularly cancer. Post-translational modifications of mA-related proteins play a fundamental role in regulating the mA methylome, thereby influencing the fate of mA-methylated RNA.

The PIN1-YTHDF1 axis promotes breast tumorigenesis via the mA-dependent stabilization of AURKA mRNA.

The post-transcriptional processing of N-methyladenosine (mA)-modified mRNA by YTH domain-containing family protein 1 (YTHDF1) plays a crucial role in the regulation of gene expression. Although YTHDF1 expression is frequently upregulated in breast cancer, the regulatory mechanisms for this remain unclear. In this study, we examined the role of peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) in regulating YTHDF1 stability in breast cancer cells.

Sirtuin 5-mediated deacetylation of TAZ at K54 promotes melanoma development.

Purpose: Nuclear accumulation of YAP/TAZ promotes tumorigenesis in several cancers, including melanoma. Although the mechanisms underlying the nuclear retention of YAP are known, those underlying the retention of TAZ remain unclear. Our study investigates a novel acetylation/deacetylation switch in TAZ, governing its subcellular localization in melanoma tumorigenesis.

Clinicoradiological Features of Pulmonary Cryptococcosis in Immunocompetent Patients.

Purpose: To assess the clinicoradiological features of pulmonary cryptococcosis in immunocompetent patients.

Materials And Methods: This retrospective study included immunocompetent patients who had been diagnosed with pulmonary cryptococcosis on the histopathologic exam and underwent chest CT between January 2008 and November 2019. Imaging features were divided into major imaging patterns, distributions, and ancillary imaging findings.

METTL3 stabilization by PIN1 promotes breast tumorigenesis via enhanced mA-dependent translation.

Methyltransferase-like 3 (METTL3) is the catalytic subunit of the N-adenosine methyltransferase complex responsible for N-methyladenosine (mA) modification of mRNA in mammalian cells. Although METTL3 expression is increased in several cancers, the regulatory mechanisms are unclear. We explored the regulatory roles of peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) in METTL3 stability and mA modification of mRNA.

Modulation of Autophagy is a Potential Strategy for Enhancing the Anti-Tumor Effect of Mebendazole in Glioblastoma Cells.

Mebendazole (MBZ), a microtubule depolymerizing drug commonly used for the treatment of helminthic infections, has been suggested as a repositioning candidate for the treatment of brain tumors. However, the efficacy of MBZ needs further study to improve the beneficial effect on the survival of those patients. In this study, we explored a novel strategy to improve MBZ efficacy using a drug combination.

Regulation of Interleukin-36γ/IL-36R Signaling Axis by PIN1 in Epithelial Cell Transformation and Breast Tumorigenesis.

Given the increasing recognition of the relationship between IL-1 cytokines, inflammation, and cancer, the significance of distinct members of the IL-1 cytokine family in the etiology of cancer has been widely researched. In the present study, we investigated the underlying mechanism of the IL-36γ/IL-36R axis during breast cancer progression, which has not yet been elucidated. Initially, we determined the effects of IL-36γ on the proliferation and epithelial cell transformation of JB6 Cl41 mouse epidermal and MCF7 human breast cancer cells using BrdU incorporation and anchorage-independent growth assays.

Potent Imidazothiazole-based Inhibitor of BRAF V600E Overcomes Acquired Resistance Inhibition of RAF Dimerization in PLX4032-resistant Melanoma.

Background/aim: The B-raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutation is frequent in patients with advanced melanoma. PLX4032, an inhibitor of BRAFV600E kinase, is effective for the treatment of melanoma in BRAF V600E-positive patients; however, resistance eventually develops due to paradoxical activation of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinases (ERK) pathway resulting from RAF dimerization. In this study, we investigated the inhibitory effects of a novel imidazothiazole-based compound, KS28, on RAF dimerization and resistance to PLX4032 in melanoma.

A multipathogen DNA vaccine elicits protective immune responses against two class A bioterrorism agents, anthrax and botulism.

The potential use of biological agents has become a major public health concern worldwide. According to the CDC classification, Bacillus anthracis and Clostridium botulinum, the bacterial pathogens that cause anthrax and botulism, respectively, are considered to be the most dangerous potential biological agents. Currently, there is no licensed vaccine that is well suited for mass immunization in the event of an anthrax or botulism epidemic.

Physiological Functions of Thiol Peroxidases (Gpx1 and Prdx2) during Embryonic Development.

Glutathione peroxidase 1 (Gpx1) and peroxiredoxin 2 (Prdx2) belong to the thiol peroxidase family of antioxidants, and have been studied for their antioxidant functions and roles in cancers. However, the physiological significance of Gpx1 and Prdx2 during vertebrate embryogenesis are lacking. Currently, we investigated the functional roles of Gpx1 and Prdx2 during vertebrate embryogenesis using as a vertebrate model.

METTL3 induces PLX4032 resistance in melanoma by promoting mA-dependent EGFR translation.

Acquired resistance often limits therapeutic efficacy of the BFAF (V600E) kinase inhibitor PLX4032 in patients with advanced melanoma. Epitranscriptomic modification of mRNAs by N-methyladenosine (mA) modification contributes to melanoma pathogenesis; however, its role in acquired PLX4032 resistance remains unexplored. Here, we showed that mA methyltransferase METTL3 expression is upregulated in A375R cells, a PLX4032-resistant subline of A375 melanoma cells, compared with the parental cells.

Discovery of New Imidazo[2,1-]thiazole Derivatives as Potent Pan-RAF Inhibitors with Promising and Anti-melanoma Activity.

BRAF is an important component of MAPK cascade. Mutation of BRAF, in particular V600E, leads to hyperactivation of the MAPK pathway and uncontrolled cellular growth. Resistance to selective inhibitors of mutated BRAF is a major obstacle against treatment of many cancer types.

IL-33-Induced Transcriptional Activation of LPIN1 Accelerates Breast Tumorigenesis.

Phospholipids are crucial materials that are not only required for cell membrane construction but also play significant roles as signaling molecules. LPIN1 is an enzyme that displays phosphatidate phosphatase activity in the triglyceride and phospholipid synthesis pathway. Recent studies have shown that overexpression of LPIN1 is involved in breast tumorigenesis, but the underlying mechanism regulating LPIN1 expression has not been elucidated yet.

Interleukin-34-CSF1R Signaling Axis Promotes Epithelial Cell Transformation and Breast Tumorigenesis.

IL-34 has been recently identified as a ligand for CSF1R that regulates various cellular processes including cell proliferation, survival, and differentiation. Although the binding of IL-34 to CSF1R modulates several cancer-driving signaling pathways, little is known about the role of IL-34/CSF1R signaling in breast cancer. Herein, we report that IL-34 induces epithelial cell transformation and breast tumorigenesis through activation of MEK/ERK and JNK/c-Jun pathways.

PIN1 facilitates ubiquitin-mediated degradation of serine/threonine kinase 3 and promotes melanoma development via TAZ activation.

The Hippo signaling pathway controls cellular processes including growth, homeostasis, and apoptosis. The kinase STK3 acts upstream in this pathway to activate LATS1/2 kinase, which phosphorylates and inactivates the transcriptional coactivators YAP/TAZ. The dysregulation of Hippo signaling leads to human diseases including cancer; however, the molecular mechanisms underlying its dysregulation in melanoma are unknown.