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UNC5A, an epigenetically silenced gene, functions as a tumor suppressor in non-small cell lung cancer.

ABSTRACT: UNC5A has been reported to be related with human cancers. However, the function and mechanism in non-small cell lung carcinoma (NSCLC) remains unknown. We analyzed two NSCLC cell lines (A549 and H157), one normal human bronchial epithelial cell line (BEAS-2B) and the tissues of NSCLC. We used quantitative real-time PCR (qRT-PCR), western blot and immunohistochemical (IHC) staining to examine the expression of UNC5A. Methylation status of the UNC5A promoter was analyzed using methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP). We used western blot to analyzed protein levels of PI3K/Akt pathway. We found that the mRNA expression of UNCA5 was significantly downregulated in NSCLC cells and tissues. The promoter of UNC5A was hypermethylated in NSCLC cells compared to normal control cells. The expression of UNC5A could be reversed by demethylation agent in NSCLC cells. The expression of UNC5A was decreased in NSCLC samples and significantly associated with the advanced types of NSCLC. Functionally, knockdown of UNC5A promoted cell proliferation, migration, invasion and induced apoptosis in NSCLC, overexpression of UNC5A yielded the opposite result. Moreover, we found that UNC5A negatively regulated PI3K/Akt signaling pathway in NSCLC. UNC5A is a novel epigenetically silenced gene in NSCLC and consequent under-expression of UNC5A may contribute to NSCLC tumorigenesis through regulating PI3K/Akt pathway.

SUBMITTER: Ding S

PROVIDER: S-EPMC7569136 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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UNC5A, an epigenetically silenced gene, functions as a tumor suppressor in non-small cell lung cancer.

Ding Silu S Zhang Hongwei H Zhao Xinyu X Dang Jun J Li Guang G

Saudi journal of biological sciences 20200917 11

UNC5A has been reported to be related with human cancers. However, the function and mechanism in non-small cell lung carcinoma (NSCLC) remains unknown. We analyzed two NSCLC cell lines (A549 and H157), one normal human bronchial epithelial cell line (BEAS-2B) and the tissues of NSCLC. We used quantitative real-time PCR (qRT-PCR), western blot and immunohistochemical (IHC) staining to examine the expression of UNC5A. Methylation status of the UNC5A promoter was analyzed using methylation-specific ...[more]

PMID: 33100860

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Project description:BackgroundTumor suppressor epigenetic silencing plays an important role in non-small cell lung cancer (NSCLC) development and progression. Previously, the expression of speckle-type POZ protein (SPOP) has been found to be significantly inhibited in NSCLC. Our research aimed to investigate the molecular mechanisms, clinical significance and epigenetic alteration of SPOP in NSCLC.Materials and methodsBisulfite sequencing PCR and methylation-specific PCR were performed to test gene methylation. Chromatin immunoprecipitation (ChIP) was performed to detect transcription factor C/EBP? combinations and the promoter of the SPOP gene. Furthermore, we evaluated the effects of C/EBP? siRNA on SPOP expression, tumor cell migration and proliferation via MTT and Transwell assays in vitro and tumor growth in vivo. The relationship between the methylation status of the SPOP gene and clinicopathologic characteristics was investigated.ResultsHypermethylation was found in the CpG island of the SPOP gene promoter in NSCLC tissues, and this methylation was found to be correlated with SPOP expression. SPOP promoter methylation was associated with the pathology grade. The transcriptional activities were significantly inhibited by the hypermethylation of specific CpG sites within the SPOP gene promoter, while 5-aza-2'-deoxycytidine significantly increased SPOP gene expression. C/EBP? also played a key role in SPOP regulation. Five C/EBP? binding sites in the CpG island of the SPOP gene promoter were identified by ChIP. Inhibition of C/EBP? significantly reduced SPOP expression. SPOP mediated the C/EBP?-regulated suppression of invasion, migration and proliferation in vitro and tumor growth in vivo.ConclusionsSPOP function and expression in NSCLS were regulated by DNA methylation and C/EBP? transcriptional regulation combination effects, indicating that the SPOP promoter methylation status could be utilized as an epigenetic biomarker and that the C/EBP?-SPOP signaling pathway could be a potential therapeutic target in NSCLC.

Dataset Information

UNC5A, an epigenetically silenced gene, functions as a tumor suppressor in non-small cell lung cancer.

Publications

UNC5A, an epigenetically silenced gene, functions as a tumor suppressor in non-small cell lung cancer.

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