A MAPK/miR-29 Axis Suppresses Melanoma by Targeting MAFG and MYBL2

Vera, Olga; Bok, Ilah; Jasani, Neel; Nakamura, Koji; Xu, Xiaonan; Mecozzi, Nicol; Angarita, Ariana; Wang, Kaizhen; Tsai, Kenneth Y.; Karreth, Florian A.

doi:10.3390/cancers13061408

Cited by 20 publications

(11 citation statements)

References 61 publications

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“… Koynovaa et al (2007) found a higher frequency of low-level increase of the copy numbers of MYBL2 rather than amplification in melanoma. Also, evidence showed that attenuation of miR-29b2∼c expression promotes the development of melanoma by partly depressing MAFG and MYBL2 ( Vera et al, 2021 ). Taken together, this evidence indicated that MYBL2 was involved in cell proliferation and tumorigenesis in melanoma, which is consistent with our present findings.…”

Section: Discussionmentioning

confidence: 99%

Identification of aberrantly methylated differentially expressed genes and pro-tumorigenic role of KIF2C in melanoma

Huang

Han

et al. 2022

Front. Genet.

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Background: Skin Cutaneous Melanoma (SKCM) is known as an aggressive malignant cancer, which could be directly derived from melanocytic nevi. However, the molecular mechanisms underlying the malignant transformation of melanocytes and melanoma tumor progression still remain unclear. Increasing research showed significant roles of epigenetic modifications, especially DNA methylation, in melanoma. This study focused on the identification and analysis of methylation-regulated differentially expressed genes (MeDEGs) between melanocytic nevus and malignant melanoma in genome-wide profiles.Methods: The gene expression profiling datasets (GSE3189 and GSE114445) and gene methylation profiling datasets (GSE86355 and GSE120878) were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and differentially methylated genes (DMGs) were identified via GEO2R. MeDEGs were obtained by integrating the DEGs and DMGs. Then, a functional enrichment analysis of MeDEGs was performed. STRING and Cytoscape were used to describe the protein-protein interaction (PPI) network. Furthermore, survival analysis was implemented to select the prognostic hub genes. Next, we conducted gene set enrichment analysis (GSEA) of hub genes. To validate, SKCM cell culture and lentivirus infection was performed to reveal the expression and behavior pattern of KIF2C. Patients and specimens were collected and then immunohistochemistry (IHC) staining was conducted.Results: We identified 237 hypomethylated, upregulated genes and 182 hypermethylated, downregulated genes. Hypomethylation-upregulated genes were enriched in biological processes of the oxidation-reduction process, cell proliferation, cell division, phosphorylation, extracellular matrix disassembly and protein sumoylation. Pathway enrichment showed selenocompound metabolism, small cell lung cancer and lysosome. Hypermethylation-downregulated genes were enriched in biological processes of positive regulation of transcription from RNA polymerase II promoter, cell adhesion, cell proliferation, positive regulation of transcription, DNA-templated and angiogenesis. The most significantly enriched pathways involved the transcriptional misregulation in cancer, circadian rhythm, tight junction, protein digestion and absorption and Hippo signaling pathway. After PPI establishment and survival analysis, seven prognostic hub genes were CKS2, DTL, KIF2C, KPNA2, MYBL2, TPX2, and FBL. Moreover, the most involved hallmarks obtained by GSEA were E2F targets, G2M checkpoint and mitotic spindle. Importantly, among the 7 hub genes, we found that down-regulated level of KIF2C expression significantly inhibited the proliferative ability of SKCM cells and suppressed the metastasis capacity of SKCM cells.Conclusions: Our study identified potential aberrantly methylated-differentially expressed genes participating in the process of malignant transformation from nevus to melanoma tissues based on comprehensive genomic profiles. Transcription profiles of CKS2, DTL, KIF2C, KPNA2, MYBL2, TPX2, and FBL provided clues of aberrantly methylation-based biomarkers, which might improve the development of precision medicine. KIF2C plays a pro-tumorigenic role and potentially inhibited the proliferative ability in SKCM.

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Section: Discussionmentioning

confidence: 99%

Identification of aberrantly methylated differentially expressed genes and pro-tumorigenic role of KIF2C in melanoma

Huang

Han

et al. 2022

Front. Genet.

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“…In this study, we report the establishment of another 4 murine melanoma cell lines and the systematic characterization of key features for the 21 cell lines. Furthermore, by inducible CRISPR/Cas9-mediated depletion of MAFG, a transcription factor we recently identified as a potential vulnerability of melanoma ( Vera et al., 2021 ), we show the utility of the integrated regulatory elements for the characterization of genes of interest.…”

Section: Introductionmentioning

confidence: 76%

“…On Dox treatment, GFP expression was reduced ( Figure 6 b), thus validating Cas9 activity. To demonstrate the utility of Dox-inducible TRE-Cas9, we delivered a sgRNA targeting Mafg to two murine melanoma lines, a transcription factor we recently found to be important for the proliferation of melanoma cells ( Vera et al., 2021 ) ( Figure 6 a). Dox treatment reduced Mafg expression in TRE-Cas9 melanoma lines harboring a Mafg -targeting sgRNA ( Figure 6 c).…”

Section: Resultsmentioning

confidence: 99%

A Series of BRAF- and NRAS-Driven Murine Melanoma Cell Lines with Inducible Gene Modulation Capabilities

et al. 2022

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…However, only MYBL2 is ubiquitously expressed in proliferating cells (12,13). The expression of MYBL2 gene is controlled by other transcription factors or noncoding RNA (41)(42)(43)(44)(45), and the MYBL2 protein is activated via phosphorylation (14,21). After activated, MYBL2 regulates downstream diverse genes or proteins involved in multiple cellular processes, such as BCL2 and MYC in cell survival (46)(47)(48), cyclins and FGF4 in cell cycle (49-51), SOX2 and OCT4 in cell differentiation (52,53), SNAIL and YAP1 in cell invasion and metastasis (19,54).…”

Section: Discussionmentioning

confidence: 99%

MYBL2 Gene Polymorphism Is Associated With Acute Lymphoblastic Leukemia Susceptibility in Children

Guo

Sun

et al. 2021

Front. Oncol.

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PurposeAlthough MYBL2 had been validated to participate in multiple cancers including leukemia, the role of MYBL2 polymorphisms in acute lymphoblastic leukemia (ALL) was still not clear. In this study, we aimed to evaluate the association between MYBL2 single nucleotide polymorphisms (SNPs) and ALL risk in children.MethodsA total of 687 pediatric ALL cases and 971 cancer-free controls from two hospitals in South China were recruited. A case-control study by genotyping three SNPs in the MYBL2 gene (rs285162 C>T, rs285207 A>C, and rs2070235 A>G) was conducted. The associations were assessed by odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Subgroup and stratification analyses were conducted to explore the association of rs285207 with ALL risk in terms of age, sex, immunophenotype, risk level, and other clinical characteristics. The false-positive report probability (FPRP) analysis was performed to verify each significant finding. Functional analysis in silico was used to evaluate the probability that rs285207 might influence the regulation of MYBL2.ResultsOur study demonstrated that rs285207 was related to a decreased ALL risk (adjusted OR = 0.78; 95% CI = 0.63-0.97, P = 0.022) in the dominant model. The associations of rs285207 with ALL risk appeared stronger in patients with pre B ALL (adjusted OR=0.56; 95% CI=0.38-0.84, P=0.004), with normal diploid (adjusted OR=0.73; 95% CI=0.57-0.95, P=0.017), with low risk (adjusted OR=0.68; 95% CI=0.49-0.94, P=0.021), with lower WBC (adjusted OR=0.62; 95% CI=0.43-0.87, P=0.007) or lower platelet level (adjusted OR=0.76; 95% CI=0.59-0.96, P=0.023). With FPRP analysis, the significant association between the rs285207 polymorphism and decreased ALL risk was still noteworthy (FPRP=0.128). Functional analysis showed that IKZF1 bound to DNA motif overlapping rs285207 and had a higher preference for the risk allele A. As for rs285162 C>T and rs2070235 A>G, no significant was found between them and ALL risk.ConclusionIn this study, we revealed that rs285207 polymorphism decreased the ALL risk in children, and rs285207 might alter the binding to IKZF1, which indicated that the MYBL2 gene polymorphism might be a potential biomarker of childhood ALL.

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A MAPK/miR-29 Axis Suppresses Melanoma by Targeting MAFG and MYBL2

Cited by 20 publications

References 61 publications

Identification of aberrantly methylated differentially expressed genes and pro-tumorigenic role of KIF2C in melanoma

Identification of aberrantly methylated differentially expressed genes and pro-tumorigenic role of KIF2C in melanoma

A Series of BRAF- and NRAS-Driven Murine Melanoma Cell Lines with Inducible Gene Modulation Capabilities

MYBL2 Gene Polymorphism Is Associated With Acute Lymphoblastic Leukemia Susceptibility in Children

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