lncRNA-PLACT1 sustains activation of NF-κB pathway through a positive feedback loop with IκBα/E2F1 axis in pancreatic cancer.

BACKGROUND: The activation of NF-kappaB signaling pathway is regarded as the dominant process that correlates with tumorigenesis. Recently, increasing evidence shows that long noncoding RNAs (lncRNAs) play crucial roles in sustaining the NF-kappaB signaling pathway. However, the underlying mechanisms have not yet been elucidated. METHODS: The expression and clinical features of PLACT1 were analyzed in a 166-case cohort of PDAC by qRT-PCR and in situ hybridization. The functional role of PLACT1 was evaluated by both in vitro and in vivo experiments. Chromatin isolation by RNA purification assays were utilized to examine the interaction of PLACT1 with IkappaBalpha promoter. RESULTS: We identified a novel lncRNA-PLACT1, which was significantly upregulated in tumor tissues and correlated with progression and poor survival in PDAC patients. Moreover, PLACT1 promoted the proliferation and invasion of PDAC cells in vitro. Consistently, PLACT1 overexpression fostered the progression of PDAC both in orthotopic and lung metastasis mice models. Mechanistically, PLACT1 suppressed IkappaBalpha expression by recruiting hnRNPA1 to IkappaBalpha promoter, which led to increased H3K27me3 that decreased the transcriptional level of IkappaBalpha. Furthermore, E2F1-mediated overexpression of PLACT1 modulated the progression of PDAC by sustained activation of NF-kappaB signaling pathway through forming a positive feedback loop with IkappaBalpha. Importantly, administration of the NF-kappaB signaling pathway inhibitor significantly suppressed PLACT1-induced sustained activation of NF-kappaB signaling pathway, leading to reduced tumorigenesis in vivo. CONCLUSIONS: Our findings suggest that PLACT1 provides a novel epigenetic mechanism involved in constitutive activation of NF-kappaB signaling pathway and may represent a new therapeutic target of PDAC.