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

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Melanocyte, Skin

DISEASE(S): Skin Melanoma

SUBMITTER: yalei wen

LAB HEAD: Yalei Wen

PROVIDER: PXD051431 | Pride | 2024-09-19

REPOSITORIES: Pride

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			Action	DRS
	U46-4.15-2.msf	Msf
	U46-4.15-2.raw	Raw
	U46-4.15-3.msf	Msf
	U46-4.15-3.raw	Raw
	WYL-CTRL-1.msf	Msf

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

Project description: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.

2024-09-20 | PXD046277 | Pride

Comparative genomic hybridization of kidney samples from Wilms tumor patients to accurately map 1p13 breakpoints

Project description:Wilms tumour karyotypes frequently exhibit recurrent, large-scale chromosomal imbalances, among the most common of which are concurrent loss of 1p and gain of 1q. We have previously identified a novel breakpoint at 1p13 by 1Mb-spaced array CGH, and undertook a fine-tiling oligonucleotide array approach to accurately map the region in four tumours exhibiting rearrangements at this locus. The use of a 10 bpspaced platform revealed that all four tumours in fact harboured different breakpoints, which were mapped to target four distinct genes PHTF1, DCLRE1B, TRIM33 and NRAS. The precise breakpoint interval was confirmed for one case to lie within intron 3 of DCLRE1B by quantitative copy number PCR and RT-PCR. In addition, expression profiling revealed a pattern of down- and up-regulation of genes either side of the breakpoint in all cases. Although it appears that no single gene is the driver of this rearrangement, this study highlights the power of fine-tiling oligonucleotide arrays to delineate breakpoint regions identified by other genome-wide screens. Processed data is provided as one archive per processed data file obtained via clicking on the ftp link. Related experiment E-TABM-164.

2007-03-21 | E-TABM-155 | biostudies-arrayexpress

An integrated multi-omics analysis of identiﬁes distinct molecular characteristics in pulmonary infections of Pseudomonas aeruginosa

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A0913 interacts with CP47 of PSII and ApcF of PBS

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