Research Article: Circular RNA circNOL10 Inhibits Lung Cancer Development by Promoting SCLM1‐Mediated Transcriptional Regulation of the Humanin Polypeptide Family

Date Published: November 16, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Aruo Nan, Lijian Chen, Nan Zhang, Yangyang Jia, Xin Li, Hanyu Zhou, Yihui Ling, Zhishan Wang, Chengfeng Yang, Sijin Liu, Yiguo Jiang.


circNOL10 is a circular RNA expressed at low levels in lung cancer, though its functions in lung cancer remain unknown. Here, the function and molecular mechanism of circNOL10 in lung cancer development are investigated using in vitro and in vivo studies, and it is shown that circNOL10 significantly inhibits the development of lung cancer and that circNOL10 expression is co‐regulated by methylation of its parental gene Pre‐NOL10 and by splicing factor epithelial splicing regulatory protein 1 (ESRP1). circNOL10 promotes the expression of transcription factor sex comb on midleg‐like 1 (SCML1) by inhibiting transcription factor ubiquitination and thus also affects regulation of the humanin (HN) polypeptide family by SCML1. circNOL10 also affects mitochondrial function through regulating the humanin polypeptide family and affecting multiple signaling pathways, ultimately inhibiting cell proliferation and cell cycle progression, and promoting the apoptosis of lung cancer cells, thereby inhibiting lung cancer development. This study investigates the functions and molecular mechanisms of circNOL10 in the development of lung cancer and reveals its involvement in the transcriptional regulation of the HN polypeptide family by SCML1. The results also demonstrate the inhibitory effect of HN on lung cancer cells growth. These findings may identify novel targets for the molecular therapy of lung cancer.

Partial Text

Lung cancer is the main cause of cancer‐related deaths worldwide, and has thus been a focus of cancer research.1 Understanding the molecular mechanisms involved in lung cancer development is therefore critical for determining its therapy and prognosis. Increasing evidence suggests the existence of a close association between epigenetics and lung cancer. However, related studies have mainly concentrated on DNA methylation and histone modification,2, 3, 4 and the roles of noncoding RNAs in lung cancer remain uncertain. However, we and others have investigated the association between noncoding RNAs and lung cancer and confirmed an important regulatory function for noncoding RNAs in epigenetics and lung cancer development.5, 6, 7

Increasing numbers of circRNAs are being identified and their functions and molecular mechanisms elucidated. circRNAs have been shown to play important roles in various cancers. circRNA MYLK can act as an endogenous competitive RNA to promote the development of bladder cancer through regulating the vascular endothelial growth factor (VEGF)A/VEGF receptor 2 signaling pathway.35 circRNACCDC66 was shown to accelerate the proliferation and metastasis of colon cancer,36 circLARP4 regulated LARP4 expression by competitively binding to miR‐424‐5p in gastric cancer,37 and circLMO7 was involved in the regulation of myogenic differentiation in cattle.38 circRNAs have also been shown to regulate the lung cancer phenotype by acting as endogenous competitive RNAs during carcinogenesis and tumor development39, 40; however, studies on the function and mechanism of circRNAs in lung cancer are still limited. As natural endogenous RNAs, circRNAs have multiple functions associated with their specific structure, and further detailed studies are needed to explore their functions and molecular mechanisms.

Cell and Animal Experiments and Human Tissue Samples: The cells used in this study were all cultured as recommended by the American Type Culture Collection. All cell lines were authenticated by short tandem repeat profiling. All the animal experiments in this study were approved by the Experimental Animal Ethics Committee of Guangzhou Medical University. The experimental animals were maintained under specific‐pathogen‐free conditions at the Experimental Animal Center of Guangzhou Medical University, and fed in accordance with the rules of the center. The BALB/c‐nu/nu mice used in this study were provided by the Guangdong Medical Laboratory Animal Center. Human tissue samples were provided by the tissue bank of the Institute of Chemical Carcinogenesis of Guangzhou Medical University, from individuals from Guangzhou City. Informed consent was obtained from all patients before sample collection. This study was approved by the Medical Ethics Committee of Guangzhou Medical University.

The authors declare no conflict of interest.




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