The RNA methyltransferase NSUN6 suppresses pancreatic cancer development by regulating cell proliferation

Yang, Ruimeng; Liang, Xing; Wang, Hui; Guo, Miaomiao; Shen, Hui; Shi, Yan-Hui; Liu, Qiang; Sun, Yongwei; Yang, Linhua; Zhan, Ming

doi:10.1016/j.ebiom.2020.103195

Cited by 64 publications

(63 citation statements)

References 39 publications

(33 reference statements)

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“…Particularly, increased NSUN6 protein level leads to the lower tumor stage and less tumor metastasis. This result agrees with previous experiments that NSUN6 is a tumor suppressor by functioning as a m5C writer in pancreatic and breast cancer cells (Selmi et al 2021, Yang et al 2021. In conclusion, the NSUN6 writer is regarded as a protective protein in colon cancer.…”

Section: Discussionsupporting

confidence: 93%

“…Recently, NSUN6 is reported to enhance the stability and translation of target mRNA, which have the consensus sequence motif CTCCA (Selmi et al 2021). The further analysis shows that NSUN6 could be a tumor suppressor in speci c cancers (Selmi et al 2021, Yang et al 2021). In comparison with other family proteins, the mRNA level of NSUN6 has the opposite tread of tumor grade and stage in gastrointestinal cancer (Xiang S. et al 2020).…”

Section: Introductionmentioning

confidence: 99%

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NSUN6 as a Key RNA Methylation Regulator in Colon Cancer

Zhao

Sun

et al. 2021

Preprint

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Background RNA methylation plays an important role in epigenetic modifications, which involves in the regulation of RNA processing, stability and translation. While the cross-talking and the mechanism of multi-type RNA methylation in colon cancer needs further investigation. Here we report the comprehensive analysis of the RNA methylation regulators for N6-methyladenosine, N1-metylasdenosine and 5-methylcytosine in the tumorigenesis and progression of colon cancer. Methods The mRNA expression and genetic mutation of 40 RNA modification regulators in patients with colon cancer were obtained from TCGA and GEO database. Consensus clustering is applied to classify the patients based on the regulator expression. The patients with different survival rates are examined for their gene mutations, biological pathways, and immune properties. The regulators with the highest vimp score are identified to be important for survival using the improved random forest analysis method. Biopsy samples from 108 patients are used to validate the key regulators using tissue microarray and specific antibodies. Finally, the mechanism underlying the methylation regulators is further examined by GSVA and correlation analysis. Results The patients are clearly clustered into two groups with different survivals. The patients with the worse survival are correlated with dysregulated KRAS signaling, hypoxia and immune responses. They are also prone to increased stromal scores and myeloid-derived suppressor cells. Markedly, m5C methyltransferase NSUN6 is identified as the most significant regulator for prognosis. The upregulated expression of NSUN6 is further proved in 108 patients by immunohistochemistry and tissue array, suggesting its association with better prognosis and lower tumor staging. Bioinformatic analysis indicates that NSUN6 enhances the expression of E3 ubiquitin ligase FBXW7, activates ubiquitin-proteolysis and suppresses oncogene expression. Conclusions Patients with colon cancer are clearly clustered into different survivals by RNA methylation regulators, and the worse prognosis is relevant to dysregulated KRAS signaling, hypoxia and immune response. NSUN6 is found to prolong the survival and strongly correlated with FBXW7 that reduces the oncogene expression and activates the ubiquitin-proteolysis.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

NSUN6 as a Key RNA Methylation Regulator in Colon Cancer

Zhao

Sun

et al. 2021

Preprint

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“…G2M checkpoint and KRAS signaling pathway have been proved to play an important role in the progression and development of liver cancer (33)(34)(35). A previous study has demonstrated biological processes related to cell proliferation like G2M checkpoint, and cell cycle were enriched in abnormal expression of RNA-methyltransferase NSUN6 (36). Furthermore, research studies have demonstrated that E2Fs are the downstream of cell cycle signaling pathway and have a significant impact in modulation of cell proliferation, differentiation, and apoptosis (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Identification METTL18 as a Potential Prognosis Biomarker and Associated With Immune Infiltrates in Hepatocellular Carcinoma

Cheng

Zhao

et al. 2021

Front. Oncol.

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Methyltransferase-like 18 (METTL18), a METTL family member, is abundant in hepatocellular carcinoma (HCC). Studies have indicated the METTL family could regulate the progress of diverse malignancies while the role of METTL18 in HCC remains unclear. Data of HCC patients were acquired from the cancer genome atlas (TCGA) and gene expression omnibus (GEO). The expression level of METTL18 in HCC patients was compared with normal liver tissues by Wilcoxon test. Then, the logistic analysis was used to estimate the correlation between METTL18 and clinicopathological factors. Besides, Gene Ontology (GO), Gene Set Enrichment Analysis (GSEA), and single-sample Gene Set Enrichment Analysis (ssGSEA) were used to explore relevant functions and quantify the degree of immune infiltration for METTL18. Univariate and Multivariate Cox analyses and Kaplan–Meier analysis were used to estimate the association between METTL18 and prognosis. Besides, by cox multivariate analysis, a nomogram was conducted to forecast the influence of METTL18 on survival rates. METTL18-high was associated with Histologic grade, T stage, Pathologic stage, BMI, Adjacent hepatic tissue inflammation, AFP, Vascular invasion, and TP53 status (P < 0.05). HCC patients with METTL18-high had a poor Overall-Survival [OS; hazard ratio (HR): 1.87, P < 0.001), Disease-Specific Survival (DSS, HR: 1.76, P = 0.015), and Progression-Free Interval (PFI, HR: 1.51, P = 0.006). Multivariate analysis demonstrated that METTL18 was an independent factor for OS (HR: 2.093, P < 0.001), DSS (HR: 2.404, P = 0.015), and PFI (HR: 1.133, P = 0.006). Based on multivariate analysis, the calibration plots and C-indexes of nomograms showed an efficacious predictive effect for HCC patients. GSEA demonstrated that METTL18-high could activate G2M checkpoint, E2F targets, KRAS signaling pathway, and Mitotic Spindle. There was a positive association between the METTL18 and abundance of innate immunocytes (T helper 2 cells) and a negative relation to the abundance of adaptive immunocytes (Dendritic cells, Cytotoxic cells etc.). Finally, we uncovered knockdown of METTL18 significantly suppressed the proliferation, invasion, and migration of HCC cells in vitro. This research indicates that METTL18 could be a novel biomarker to evaluate HCC patients’ prognosis and an important regulator of immune responses in HCC.

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“…Yang et al recently revealed that m 5 C methyltransferase NSUN6 is downregulated in pancreatic cancer and suppressed pancreatic cancer cell proliferation and tumor growth in xenograft mouse models. Notably, NSUN6 has also been reported to play an essential role in predicting pancreatic cancer recurrence and patient survival time 123 . Another study showed that ALKBH3 is a 1-methyladenosine (m 1 A) and 3-methylcytidine (m 3 C) demethylase of transfer RNA (tRNA) and can increase cancer cell proliferation, migration, and invasion 124 .…”

Section: Discussionmentioning

confidence: 99%

N⁶-methyladenosine (m⁶A) in pancreatic cancer: Regulatory mechanisms and future direction

Wang

Liu

et al. 2021

Int. J. Biol. Sci.

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N 6 -methyladenosine (m 6 A), the most abundant RNA modification in eukaryotes, plays a pivotal role in regulating many cellular and biological processes. Aberrant m 6 A modification has recently been involved in carcinogenesis in various cancers, including pancreatic cancer. Pancreatic cancer is one of the deadliest cancers. It is a heterogeneous malignant disease characterized by a plethora of diverse genetic and epigenetic events. Increasing evidence suggests that dysregulation of m 6 A regulatory factors, such as methyltransferases, demethylases, and m 6 A-binding proteins, profoundly affects the development and progression of pancreatic cancer. In addition, m 6 A regulators and m 6 A target transcripts may be promising early diagnostic and prognostic cancer biomarkers, as well as therapeutic targets. In this review, we highlight the biological functions and mechanisms of m 6 A in pancreatic cancer and discuss the potential of m 6 A modification in clinical applications.

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The RNA methyltransferase NSUN6 suppresses pancreatic cancer development by regulating cell proliferation

Cited by 64 publications

References 39 publications

NSUN6 as a Key RNA Methylation Regulator in Colon Cancer

NSUN6 as a Key RNA Methylation Regulator in Colon Cancer

Identification METTL18 as a Potential Prognosis Biomarker and Associated With Immune Infiltrates in Hepatocellular Carcinoma

N⁶-methyladenosine (m⁶A) in pancreatic cancer: Regulatory mechanisms and future direction

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The RNA methyltransferase NSUN6 suppresses pancreatic cancer development by regulating cell proliferation

Cited by 64 publications

References 39 publications

NSUN6 as a Key RNA Methylation Regulator in Colon Cancer

NSUN6 as a Key RNA Methylation Regulator in Colon Cancer

Identification METTL18 as a Potential Prognosis Biomarker and Associated With Immune Infiltrates in Hepatocellular Carcinoma

N6-methyladenosine (m6A) in pancreatic cancer: Regulatory mechanisms and future direction

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N⁶-methyladenosine (m⁶A) in pancreatic cancer: Regulatory mechanisms and future direction