Exosome-transmitted lncRNA UFC1 promotes non-small-cell lung cancer progression by EZH2-mediated epigenetic silencing of PTEN expression

Abstract

Long non-coding RNAs (LncRNAs) have been suggested as important regulators of cancer development and progression in non-small cell lung cancer (NSCLC). Nevertheless, the biological roles and clinical significance of lncRNA UFC1 in NSCLC remain unclear. We detected the expression of UFC1 in tumor tissues, serum, and serum exosomes of NSCLC patients by qRT-PCR. Gene overexpression or silencing were used to examine the biological roles of UFC1 in NSCLC. RNA immunoprecipitation and ChIP assays were performed to evaluate the interaction between UFC1 and enhancer of zeste homolog 2 (EZH2) and the binding of EZH2 to PTEN gene promoter. Rescue study was used to access the importance of PTEN regulation by UFC1 in NSCLC progression. UFC1 expression was upregulated in tumor tissues, serum, and serum exosomes of NSCLC patients and high level of UFC1 was associated with tumor infiltration. UFC1 knockdown inhibited NSCLC cell proliferation, migration and invasion while promoted cell cycle arrest and apoptosis. UFC1 overexpression led to the opposite effects. Mechanistically, UFC1 bound to EZH2 and mediated its accumulation at the promoter region of PTEN gene, resulting in the trimethylation of H3K27 and the inhibition of PTEN expression. UFC1 knockdown inhibited NSCLC growth in mouse xenograft tumor models while the simultaneous depletion of PTEN reversed this effect. NSCLC cells derived exosomes could promote NSCLC cell proliferation, migration and invasion through the transfer of UFC1. Moreover, Exosome-transmitted UFC1 promotes NSCLC progression by inhibiting PTEN expression via EZH2-mediated epigenetic silencing. Exosome-mediated transmit of UFC1 may represent a new mechanism for NSCLC progression and provide a potential marker for NSCLC diagnosis.

The Biological Roles of Exosomal Long Non-Coding RNAs in Cancers

“…Exosomal lncRNA UFC1 promoted the progression of NSCLC through EZH2-mediated epigenetic silencing of PTEN expression, which provided a potential marker for the diagnosis of NSCLC. 32 The blood plasma levels of exosomal lncRNA SOX2-OT in post-operative patients with squamous cell lung cancer was significantly decreased, and exosomal lncRNA SOX2-OT was expected to become a non-invasive plasma marker of squamous cell lung cancer. 60 Exosomal lncRNA MALAT-1 in the serum promoted the proliferation and migration of NSCLC cells, which laid a foundation for the use of exosomal lncRNA MALAT-1 as a non-invasive serum-based biomarker for the diagnosis and prognosis of NSCLC.…”

“…In addition, exosomal lncRNA UFC1 inhibited PTEN expression and activated the Akt pathway through EZH2-mediated epigenetic silencing, promoting the progression of NSCLC. 32 In NSCLC, the expression of lncRNA MALAT-1 in the serum was upregulated after being protected by exosomes, promoting cell proliferation and migration. 33 Bioactive lncRNA PCa-specific expression and EZH2-associated transcript (PCSEAT) was bound to the exosome and passed on to neighboring cells, promoting cell proliferation and movement in prostate cancer.…”

Trends in Research on Exosomes in Cancer Progression and Anticancer Therapy

“…EMT was induced by exosomal miR-663b in bladder cancer [ 81 ]; lncRNA SOX2 overlapping transcript (Sox2ot) in pancreatic ductal adenocarcinoma (PDAC cells) [ 82 ]; and TGF-β-enriched TEXs in myofibroblasts [ 83 ]. Migration of tumor cells was facilitated by the exosome-mediated transfer of αvβ6 in prostate cancer [ 84 ]; miR-21 in bladder cancer [ 85 ]; TAM derived exosomes in gastric cancer (GC) cells [ 86 ]; and lncRNA ubiquitin-fold modifier conjugating enzyme 1 (UFC1) in non-small cell lung carcinoma (NSCLC) [ 87 ]. Exosomal lncRNA zinc finger antisense 1 (ZFAS1) induced EMT and migration in GC cells [ 88 ].…”

Biological functions and clinical applications of exosomal long non‐coding RNAs in cancer

“…is transferred to receptor cells and induces their growth. 72 MALAT1 from exosomes promotes the proliferation of breast cancer cells and NSCLC cells. 73,74 In multiple myeloma, exosomal LINC00461 has been reported to enhance cell proliferation via binding to miR-15a/16 and promoting the expression of BCL-2.…”

“…It interacts with EZH2 to regulate the H3K27me3 levels of PTEN promoter region. Exosomal UFC1 is transferred to receptor cells and induces their growth 72 …”