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Pharmacological Targeting of Casein Kinase 1δ Suppresses Oncogenic NRAS-Driven Melanoma

ABSTRACT: Activating mutations in NRAS account for 20-30% of melanoma, yet effective anti-NRAS therapies are still lacking. In this study, we unveil the casein kinase 1δ (CK1δ) as an uncharacterized regulator of oncogenic NRAS mutations, specifically Q61R and Q61K, which are the most prevalent NRAS mutations in melanoma. The genetic ablation or pharmacological inhibition of CK1δ markedly destabilizes NRAS mutants and suppresses their oncogenic functions. Moreover, we identify USP46 as a bona fide deubiquitinase of NRAS mutants. Mechanistically, CK1δ directly phosphorylates USP46 and activates its deubiquitinase activity towards NRAS mutants, thus promoting oncogenic NRAS-driven melanocyte malignant transformation and melanoma progression in vitro and in vivo. Our findings underscore the significance of the CK1δ-USP46 axis in stabilizing oncogenic NRAS mutants and provide preclinical evidence that targeting this axis holds promise as a therapeutic strategy for human melanoma harboring NRAS mutations.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Melanocyte, Cell Culture

DISEASE(S): Melanoma

SUBMITTER: yalei wen

LAB HEAD: Tongzheng Liu

PROVIDER: PXD046277 | Pride | 2024-09-20

REPOSITORIES: Pride

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			Action	DRS
	NRAS-YONG.raw	Raw
	USP46.raw	Raw
	proteinGroups-NRAS.txt	Txt
	proteinGroups-USP46.txt	Txt

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Pharmacological Targeting of Casein Kinase 1δ Suppresses Oncogenic NRAS-Driven Melanoma

Project description:Activating mutations in NRAS account for 15-20% of melanoma, yet effective anti-NRAS therapies are still lacking. In this study, we unveil the casein kinase 1δ (CK1δ) as an uncharacterized regulator of oncogenic NRAS mutations, specifically Q61R and Q61K, which are the most prevalent NRAS mutations in melanoma. The genetic ablation or pharmacological inhibition of CK1δ markedly destabilizes NRAS mutants and suppresses their oncogenic functions. Moreover, we identify USP46 as a bona fide deubiquitinase of NRAS mutants. Mechanistically, CK1δ directly phosphorylates USP46 and activates its deubiquitinase activity towards NRAS mutants, thus promoting oncogenic NRAS-driven melanocyte malignant transformation and melanoma progression in vitro and in vivo. Our findings underscore the significance of the CK1δ-USP46 axis in stabilizing oncogenic NRAS mutants and provide preclinical evidence that targeting this axis holds promise as a therapeutic strategy for human melanoma harboring NRAS mutations.

2024-09-19 | PXD051431 | Pride

Gene expression profiling of oncogenic NRAS driven mouse melanomas that have developed resistance to NRAS withdrawal

Project description:Targeted therapies have the potential to revolutionize cancer care by providing personalized treatment strategies that are less toxic and more effective but it is clear that for most solid tumors suppression of a single target is not sufficient to prevent development of resistance. A powerful method to identify mechanisms of resistance and targets for combination therapy is to use an in vivo genetic approach. We have developed a novel retroviral gene delivery mouse model of melanoma that permits control of gene expression post-delivery using the tetracycline (tet)-regulated system. In this study we used this melanoma model to select for resistant tumors following genetic inhibition of mutant NRAS. Analysis of tumors that became resistant to NRAS suppression revealed that the most common mechanism of resistance was overexpression of the Met receptor tyrosine kinase (RTK). Importantly, inhibition of Met overcomes NRAS resistance in this context. Analysis of NRAS mutant human melanoma cells revealed that inhibition of MEK is also associated with adaptive RTK signaling. Furthermore, co-inhibition of RTK signaling and MEK overcomes acquired MEK inhibitor resistance in NRAS mutant melanoma. These data suggest that combined inhibition of RTK and MEK signaling is a rational therapeutic strategy in mutant NRAS driven melanoma. Reversible NRAS Q61R expression in the melanocytes of DCT-TVA;Ink4a/Arf lox/lox mice (FVB/n) was achieved by transducing the animals with Tet-off and TRE-NRASQ61R-IRES-Cre avian leukosis viruses. After tumor initiation, the expression of NRAS Q61R was turned off by administrating doxycycline. Despite initial regression, tumors in 40% of mice developed resistance to NRAS Q61R withdraw. Seven resistant tumors and one control tumor where NRAS Q61R expression was not interrupted were subjected to genome-wide gene expression profiling.

2014-10-31 | E-GEOD-51906 | biostudies-arrayexpress

RNA sequencing analysis of Nras mutant MEFs

Project description:Purpose: Emerging evidence in the field of RAS biology is beginning to illustrate that RAS mutations are functionally distinct. To elucidate functional differences between NRAS mutants we performed RNA-sequencing on mouse embryonic fibroblasts (MEFs) expressing different NRAS codon 61 variants from the endogenous gene locus Methods: MEFs were isolated from Tyr::CRE-ERT2 LSL-Nras mouse models containing different Nras variants in the endogeous gene locus. NRAS expression was induced in MEFs using an Adenoviral Cre delivery system. RNA was isolated from MEFs six days post-NRAS induction and submitted for RNA-sequencing Results: Differential expression and gene set enrichment analysis (GSEA) between NRAS variants revealed enrichment of transcripts associated with cellular proliferation between all mutant Nras alleles versus wild-type Nras. Further, MEFs expressing NRAS mutants capable of driving melanoma formation were enriched for transcripts associated with RAS-MYC signaling axis. Conclusion: While all NRAS mutants are capable of enhancing cellular proliferation versus wild-type NRAS, the melanomagenic potential of these mutants correlates with the ability to enhance activation of the RAS-MYC signaling axis

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Effect of DNMT3A R882H mutation or WT on gene expression in hematopoietic stem/progenitor cells with NRAS G12D co-transduction (Microarray)

Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational â??hotspotâ?? at Arg882 (i.e., DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of â??stemnessâ?? gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided microarray data showing effect of R882H-mutated or WT DNMT3A on gene expression among HSPCs with NRAS G12D co-transduction. Microarray analysis of Lin- enriched hematopoietic stem/progenitor cells with retroviral infection of NRAS G12D alone (EV-RAS), DNMT3A R882H with NRAS G12D (RH-RAS) or DNMT3A WT with NRAS G12D (WT-RAS) at day 12 or day 16 post-transduction.

2016-06-23 | E-GEOD-71437 | biostudies-arrayexpress

Data independent MS phenotyping of melanoma tissue specimens

Project description:Phenotyping of Stage III BRAF or NRAS mutant melanoma tissue specimens to predict drug response and patient survival

2018-10-11 | PXD007083 | Pride

Effect of DNMT3A R882H mutation or WT expression on global DNA methylation patterns of hematopoietic stem/progenitor cells with NRAS G12D co-transduction (eRRBS)

Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational âhotspotâ at Arg882 (DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of âstemnessâ gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided enhanced Reduced Representation Bisulfite Sequencing (eRRBS) DNA methylome profiling data showing effect of DNMT3A R882H mutation or WT expression on hematopoietic stem/progenitor cells with NRAS G12D co-transduction. eRRBBs DNA methylome analysis of Lin- enriched hematopoietic stem/progenitor cells with retroviral infection of NRAS G12D alone (EV-RAS), DNMT3A R882H with NRAS G12D (RH-RAS) or DNMT3A WT with NRAS G12D (WT-RAS) at day 16 post-transduction.

2016-06-23 | E-GEOD-71473 | biostudies-arrayexpress

Effect of DNMT3A R882H mutation or WT expression on epigenetic landscapes of hematopoietic stem/progenitor cells with NRAS G12D co-transduction (ChIP-seq)

Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational âhotspotâ at Arg882 (DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of âstemnessâ gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided H3K4me1, H3K27ac and H3K79me2 ChIP-seq profiling data showing effect of DNMT3A R882H mutation or WT expression on epigenetic landscapes of hematopoietic stem/progenitor cells with NRAS G12D co-transduction. ChIP-seq analysis of Lin- enriched hematopoietic stem/progenitor cells with retroviral infection of NRAS G12D alone (EV-RAS), DNMT3A R882H with NRAS G12D (RH-RAS) or DNMT3A WT with NRAS G12D (WT-RAS) 3 weeks post-transduction. Antibodies of H3K4me1, H3K27ac and H3K79me2 were used.

2016-06-23 | E-GEOD-71472 | biostudies-arrayexpress

RNA sequencing expression analysis of murine MLL-AF9;NRAS acute myeloid leukemia cells silenced for E2-2.

Project description:We investigated the role of the transcriptional regulators Id2 and E2-2 (encoded by Tcf4) in the context of MLL-rearranged acute myeloid leukemia (AML). Using an AML mouse model driven by a Tet-off inducible MLL-AF9 allele co-expressed with oncogenic NRASG12D, we demonstrated that MLL-AF9 regulates the E protein pathway by suppressing Id2, while activating the expression of its target E2-2. Moreover, we found that Id2 over-expression in MLL-AF9 AML cells results inhibition of leukemia growth, loss of leukemia stem cell-associated gene expression pattern and induction of differentiation. E2-2 silencing phenocopies Id2 overexpression in MLL-AF9-AML cells. To study the gene expression changes associated with E2-2 depletion in the context of MLL-rearranged AML, RNA sequencing analysis was performed on MLL-AF9;NRAS AML cells transduced with vectors expressing hairpins against E2-2 (shTcf4#654 and shTcf4#3646) or a control hairpin against Renilla luciferase (shRen). Primary AMLs driven by MLL/AF9 expression linked to cherry reporter, in association with oncogenic NRASG12D (MLL/AF9;NRAS) were generated by reconstituting lethally irradiated congenic mice with fetal liver cells co-transduced with the MSCV-MLL/AF9-IRES-cherry retroviral vector and a second vector co-expressing NRASG12D together with luciferase (MSCV-luciferase-IRES-NRASG12D). RNA sequencing analysis sequencing analysis was performed on MLL-AF9;NRAS AML cells transduced in vitro with vectors expressing hairpins against E2-2 (shTcf4#654 and shTcf4#3646) or a control hairpin against Renilla luciferase (shRen) linked to the reporter GFP. Viable GFP-positive cells were FACS-sorted 2 days after transduction and used for RNA sequencing analysis. Two independent biological replicates of the experiment were used for the RNA sequencing (9-5-14 and 14-4-14).

2016-06-29 | E-GEOD-80745 | biostudies-arrayexpress

Transcriptional targets of oncogenic RAS proteins that mediate their ability to induce cellular transformation

Project description:Mutations in the NRAS oncogene are present in up to 20% of melanoma. Here, we show that interferon alpha-inducible protein 6 (IFI6) is necessary for NRASQ61K-induced transformation and melanoma growth. IFI6 was transcriptionally upregulated by NRASQ61K, and knockdown of IFI6 resulted in DNA replication stress due to dysregulated DNA replication via E2F2. This stress consequentially inhibited cellular transformation and melanoma growth via senescence or apoptosis induction depending on the RB and p53 pathway status of the cells. NRAS-mutant melanoma were significantly more resistant to the cytotoxic effects of DNA replication stress-inducing drugs, and knockdown of IFI6 increased sensitivity to these drugs. Pharmacological inhibition of IFI6 expression by the MEK inhibitor trametinib, when combined with DNA replication stress-inducing drugs, blocked NRAS-mutant melanoma growth. Collectively, we demonstrate that IFI6, via E2F2 regulates DNA replication and melanoma development and growth, and this pathway can be pharmacologically targeted to inhibit NRAS-mutant melanoma. MEL-ST cells expressing either empty vector or mutant oncogenic RAS genes (HRAS v12, KRAS v12, NRAS Q61K) were used to isolate total RNA. The RNA was then used to perform gene expression analyses using the Illumina HumanHT-12 V4.0 Expression BeadChip array.

2016-09-08 | E-GEOD-62827 | biostudies-arrayexpress

Effects of altered expression and activity levels of casein kinase 1δ and ε on tumor growth and survival of colorectal cancer patients

Project description:Colorectal cancer (CRC) is the fourth leading cause of cancer-related death worldwide due to high apoptotic resistance and metastatic potential. Since mutations as well as deregulation of CK1 isoforms contribute to tumor development and progression, CK1 has become an interesting drug target. In this study, we show that CK1 isoforms are differently expressed in colon tumor cell lines and that growth of these cell lines can be inhibited by CK1-specific inhibitors. Furthermore, expression of CK1δ and ε is changed in colorectal tumors and high CK1ε expression levels significantly correlate with prolonged patients' survival. In addition to changes in CK1δ and ε expression, mutations within exon 3 of CK1δ were detected in colorectal tumors. These mutations influence ATP binding, leading to changes in the kinetic parameters. Overexpression of these mutants in HT29 cells alters their ability to grow anchorage independently. Consistent with these results, these CK1δ mutants lead to differences in proliferation rate and tumor size in xenografts due to changes in gene expression, especially in genes involved in regulation of cell proliferation, cell cycle, and apoptosis. In summary, our results provide evidence that changes in the expression levels of CK1 isoforms in colorectal tumors correlate with the survival of patients and that CK1δ mutations affect growth and proliferation of tumor cells and induced tumor growth in xenografts, leading to the assumption that CK1 isoforms provide interesting targets in new colorectal cancer therapy concepts.

2017-05-19 | GSE57840 | GEO

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