lncRNA-PLACT1 sustains activation of NF-κB pathway through a positive feedback loop with IκBα/E2F1 axis in pancreatic cancer
Authors: Yuming Luo
Changhao Chen
Rufu Chen
Yuting Li
Min Li
Huilin Ye
Mingyang Liu
Shangyou Zheng
Zhihua Li
Zhiqiang Fu
Xiaofan Ren
Journal: Molecular Cancer (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: IκBα; Long noncoding RNA; NF-κB signaling pathway; Pancreatic ductal adenocarcinoma; Positive feedback loop.
Affiliations: Department of Medical Oncology, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, 107th Yanjiangxi Road, Yuexiu District, Guangzhou, Guangdong province, 510120, People's Republic of China., Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, 107th Yanjiangxi Road, Yuexiu District, Guangzhou, 510120, Guangdong province, People's Republic of China., Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, 107th Yanjiangxi Road, Yuexiu District, Guangzhou, 510120, Guangdong province, People's Republic of China. ., Department of Urology, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, 107th Yanjiangxi Road, Yuexiu District, Guangzhou, Guangdong province, 510120, People's Republic of China. ., Department of Hepatopancreatobiliary Surgery, Sun Yat-sen Memorial Hospital, 107th Yanjiangxi Road, Yuexiu District, Guangzhou, 510120, Guangdong province, People's Republic of China., Department of Medicine, Department of Surgery, the University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1262A, Oklahoma City, OK, 73104, USA., Department of Medicine, Department of Surgery, the University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1262A, Oklahoma City, OK, 73104, USA. ., Department of Medical Oncology, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, 107th Yanjiangxi Road, Yuexiu District, Guangzhou, Guangdong province, 510120, People's Republic of China. ., Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106th of 2nd Zhongshan Road, Yuexiu District, Guangzhou, Guangdong Province, 510080, People's Republic of China. .

Abstract:  Background: The activation of NF-κB 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-κB 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 IκBα 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 IκBα expression by recruiting hnRNPA1 to IκBα promoter, which led to increased H3K27me3 that decreased the transcriptional level of IκBα. Furthermore, E2F1-mediated overexpression of PLACT1 modulated the progression of PDAC by sustained activation of NF-κB signaling pathway through forming a positive feedback loop with IκBα. Importantly, administration of the NF-κB signaling pathway inhibitor significantly suppressed PLACT1-induced sustained activation of NF-κB 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-κB signaling pathway and may represent a new therapeutic target of PDAC. 

Retracted: No

PubPeer comments:
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