The mechanisms through which tumor cells genetically lose antigenicity and evade immune checkpoints remain largely elusive. Here, we report that tissue-specific expression of the human long-noncoding RNA LINK-A in mouse mammary glands initiated metastatic mammary gland tumors, which phenotypically resembled 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 (PKA)-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48–polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A-locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb, and p53, and sensitized mammary gland tumors to immune checkpoint blockers (ICBs). Importantly, PD-1 blockade-resistant TNBC patients exhibited elevated LINK-A levels and downregulated PLC components. Hence, we demonstrated lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which may provide the basis for developing a therapeutic regimen of combinational immunotherapy and effective early prevention for TNBCs.
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. Noncoding RNAs represent the majority of the transcriptome, with long noncoding RNAs (lncRNAs) making up a significant proportion. It has been suggested that lncRNAs play a key role in all stages of tumorigenesis and metastasis. This review will provide an overview of how lncRNAs are involved in cancer cell colonization in specific organ sites and the underlying mechanisms as well as therapeutic strategies.
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 PTEN K27-polyUb). Genetic inhibition of PTEN K27-polyUb alleviated Col4a3 knockout-, folic acid-, and streptozotocin-induced (STZ-induced) kidney injury. Serum and urine PTEN K27-polyUb concentrations were negatively correlated with glomerular filtration rate (GFR) for diabetic patients. Mechanistically, PTEN K27-polyUb facilitated dephosphorylation and protein stabilization of TWIST, SNAI1, and YAP in renal epithelial cells, leading to enhanced EMT. We identified that a small molecule, triptolide, inhibited MEX3C-catalyzed PTEN K27-polyUb and EMT of renal epithelial cells. Treatment with triptolide reduced TWIST, SNAI1, and YAP concurrently and improved kidney health in Col4a3 knockout-, folic acid-injured disease models and STZ-induced, BTBR ob/ob diabetic nephropathy models. Hence, we demonstrated the important role of PTEN K27-polyUb in DKD and a promising therapeutic strategy that inhibited the progression of DKD.
Dystrophin proteomic regulation in Muscular Dystrophies (MD) remains unclear. We report that a long noncoding RNA (lncRNA), H19 , associates with dystrophin and inhibits E3 ligase-dependent poly-ubiquitination at Lys3584 (referred to as Ub-DMD) and its subsequent protein degradation. In-frame deletions in BMD and a DMD non-silent mutation (C3340Y) result in defects in the protein’s ability to interact with H19 , causing elevated Ub-DMD levels and dystrophin degradation. Dmd C3333Y mice exhibited progressive muscular dystrophy, elevated serum CK, heart dilation, blood vessel irregularity, and respiratory failure with concurrently reduced dystrophin and increased Ub-DMD status. H19 RNA oligonucleotides conjugated with Agrin (AGR- H19 ) and Nifenazone competed-with/inhibited TRIM63. Dmd C3333Y animals, iPSC-derived skeletal muscle cells from BMD patients, or mdx mice subjected to exon-skipping exhibited inhibited dystrophin degradation, preserved skeletal/cardiac muscle histology, and improved strength/heart function following AGR- H19 or Nifenazone treatment. Our study paves the way to meaningful targeted therapeutics for BMD and certain DMD patients.
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