Hormonal therapies up-regulate MANF and overcome female susceptibility to immune checkpoint inhibitor myocarditis.

Immune checkpoint inhibitors (ICIs) have been increasingly used in combination for cancer treatment but are associated with myocarditis. Here, we report that tumor-bearing mice exhibited response to treatment with combinatorial anti-programmed cell death 1 and anti-cytotoxic T lymphocyte antigen-4 antibodies but also presented with cardiovascular toxicities observed clinically with ICI therapy, including myocarditis and arrhythmia. Female mice were preferentially affected with myocarditis compared to male mice, consistent with a previously described genetic model of ICI myocarditis and emerging clinical data.

Functional significance of gain-of-function H19 lncRNA in skeletal muscle differentiation and anti-obesity effects.

Background: Exercise training is well established as the most effective way to enhance muscle performance and muscle building. The composition of skeletal muscle fiber type affects systemic energy expenditures, and perturbations in metabolic homeostasis contribute to the onset of obesity and other metabolic dysfunctions. Long noncoding RNAs (lncRNAs) have been demonstrated to play critical roles in diverse cellular processes and diseases, including human cancers; however, the functional importance of lncRNAs in muscle performance, energy balance, and obesity remains elusive.

A noncoding RNA modulator potentiates phenylalanine metabolism in mice.

The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA and human associate with phenylalanine hydroxylase (PAH). -knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU.

The lncRNA H19 alleviates muscular dystrophy by stabilizing dystrophin.

Dystrophin proteomic regulation in muscular dystrophies (MDs) remains unclear. We report that a long noncoding RNA (lncRNA), H19, associates with dystrophin and inhibits E3-ligase-dependent polyubiquitination at Lys 3584 (referred to as Ub-DMD) and its subsequent protein degradation. In-frame deletions in BMD and a DMD non-silent mutation (C3340Y) resulted in defects in the ability of the protein to interact with H19, which caused elevated Ub-DMD levels and dystrophin degradation.

Long noncoding RNA loss in immune suppression in cancer.

Long noncoding RNAs (lncRNAs) have multiple functions in the regulation of cellular homeostasis. In recent years, numerous studies have shown that tumor-associated lncRNAs play key roles in promoting and maintaining tumor initiation and progression by shaping the tumor microenvironment through changing tumor cell intrinsic properties. Here, we focus on the roles of lncRNAs in cancer immunology.

LncRNAs as tumor cell intrinsic factors that affect cancer immunotherapy.

Long noncoding RNAs (lncRNAs) have been found to associate with all major types of malignancies and play important roles in regulating several hallmarks of cancer by interacting with proteins, DNA, and RNA. The possible functions of lncRNAs and their roles in the regulation of tumour growth will be reported and discussed in the present review. In our recent report, based on genetic mice models and a series of systematic analyses, we suggested that lncRNAs also play critical roles in the regulation of antigen presentation in tumour cells and allow tumour cells to escape immune surveillance, which further broadens the scope of understanding lncRNA functions and how they relate to cancer immunotherapy resistance.

Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression.

How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissue-specific expression of the human long noncoding RNA LINK-A in mouse mammary glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71.

PTEN-induced partial epithelial-mesenchymal transition drives diabetic kidney disease.

Epithelial-mesenchymal transition (EMT) contributes significantly to interstitial matrix deposition in diabetic kidney disease (DKD). However, detection of EMT in kidney tissue is impracticable, and anti-EMT therapies have long been hindered. We reported that phosphatase and tensin homolog (PTEN) promoted transforming growth factor beta 1 (TGF-β), sonic hedgehog (SHH), connective tissue growth factor (CTGF), interleukin 6 (IL-6), and hyperglycemia-induced EMT when PTEN was modified by a MEX3C-catalyzed K27-linked polyubiquitination at lysine 80 (referred to as PTENK27-polyUb).

LncRNAs-directed PTEN enzymatic switch governs epithelial-mesenchymal transition.

Despite the structural conservation of PTEN with dual-specificity phosphatases, there have been no reports regarding the regulatory mechanisms that underlie this potential dual-phosphatase activity. Here, we report that K27-linked polyubiquitination of PTEN at lysines 66 and 80 switches its phosphoinositide/protein tyrosine phosphatase activity to protein serine/threonine phosphatase activity. Mechanistically, high glucose, TGF-β, CTGF, SHH, and IL-6 induce the expression of a long non-coding RNA, GAEA (Glucose Aroused for EMT Activation), which associates with an RNA-binding E3 ligase, MEX3C, and enhances its enzymatic activity, leading to the K27-linked polyubiquitination of PTEN.

Molecular mechanisms of long noncoding RNAs-mediated cancer metastasis.

Cancer metastasis is a multistep process that requires cancer cells to leave the primary site, survive in the blood stream, and finally colonize at a distant organ. It is the major cause of cancer morbidity and mortality. The organ-specific colonization requires close interaction and communication between cancer cells and host organs.