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A First-In-Class Inhibitor of Skp1-Skp2 Interaction Has Potent Preclinical Efficacy Against Castration-Resistant Prostate Cancer

ABSTRACT: A First-In-Class Inhibitor of Skp1-Skp2 Interaction Has Potent Preclinical Efficacy Against Castration-Resistant Prostate Cancer

PROVIDER: PRJNA1021529 | ENA |

REPOSITORIES: ENA

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			Action	DRS
		Other
	SRR26190653_1.fastq.gz	Fastqsanger.gz
	SRR26190653_2.fastq.gz	Fastqsanger.gz
	SRR26190655_1.fastq.gz	Fastqsanger.gz
	SRR26190655_2.fastq.gz	Fastqsanger.gz

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A First-In-Class Inhibitor of Skp1-Skp2 Interaction Has Potent Preclinical Efficacy Against Castration-Resistant Prostate Cancer

Project description:Metastatic, castration-resistant prostate cancer (mCRPC) directly contributes to the mortality and morbidity of prostate cancer. It is imperative to identify new molecular targets and discover effective therapeutic agents against lethal mCRPC. We have developed a new class of small-molecule compounds and evaluated their anticancer activities in preclinical models using molecular, cellular, and animal approaches. GH501 demonstrates nanomolar potency in the NCI-60 human cancer cell panel and multiple mCRPC cell lines with diverse genetic backgrounds, including those resistant to androgen deprivation therapy drugs. Mechanistically, GH501 may bind S-phase kinase-associated protein 1 (Skp1) and disrupt the physical interaction between Skp1 and S-phase kinase-associated protein 2 (Skp2) within the Skp1-Cullin1-F-box protein ubiquitin ligase complexes (SCF), thereby affecting multiple oncogenic signals implicated in mCRPC progression, including p21, p27, β-catenin, cyclin D1, E2F1, enhancer of zeste homolog 2, c-Myc, and survivin. GH501 exhibits excellent in vitro and in vivo safety pharmacology, and GH501 monotherapy effectively inhibits the in vivo growth of cell- and patient-derived xenografts in intraosseous and subcutaneous models. These results indicate that GH501 is a promising therapeutic candidate for the treatment of mCRPC and warrants further preclinical development.

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MDAMB231 transcriptome response to SKP2 knockdown

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SKP2-affinity-purified mass spectrometry analysis.

Project description:This project aims to identify the SKP2 interaction proteins.

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comparison_col0vsskp2-Functional analysis of the SKP2 and CUL4 proteins

Project description:rs04-04_skp2_cul4 - comparison_col0vsskp2 - Antisense and mutants of the SKP2 and CUL4 genes are compared to the Wt in order to identify the genes controlled by those SCF proteins. - Comparison Col0 versus skp2

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SKP2 knockout in Rb1/p53 deficient transgenic mouse models of osteosarcoma induces macrophage infiltration and drives transcription of genes with favorable prognosis in patients

Project description:To study SKP2 in osteosarcoma, we generated a Skp2 KO line and a Skp2 intact line of transgenic OS mouse models: germline Skp2 knockout (“TKO”: Osx1-Cre;Rb1lox/lox;p53lox/lox;SKP2) versus Skp2 intact (“DKO”: Osx1-Cre;Rb1lox/lox;p53lox/lox). We then performed bulk RNAseq of the SKP2 KO vs SKP2 intact OS.

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Murine hamatopoietic stem cell (HSC): wild type and Skp2 knockout

Project description:Transcriptional profiling of mouse HSC comparing wild type (WT) and Skp2 knockout Collected bone marrow (BM) cells from WT and Skp2 knockout mice, stained with HSC surface markers for FACS. Collected HSC and extracted total RNA then sent out for microarray analysis.

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MDAMB231 transcriptome response to SKP2 knockdown

Project description:MDAMB231 transcriptome response to SKP2 knockdown

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Project description:Rhabdomyosarcoma (RMS) is a pediatric mesenchymal-derived malignancy encompassing Fusion Positive (FP)-RMS expressing PAX3/7-FOXO1 and Fusion Negative (FN)-RMS often mutated in the RAS pathway. RMS expresses the master myogenic transcription factor MYOD that, paradoxically, is unable to support differentiation while essential for tumor cell survival. We identify here SKP2, an oncogenic E3-ubiquitin ligase, as a critical driver of tumorigenesis in FN-RMS. SKP2 is overexpressed in RMS at the highest levels among several adult and pediatric cancers and its expression is maintained by MYOD through an intronic enhancer within the gene. In FN-RMS SKP2 promotes cell cycle progression and prevents differentiation directly targeting p27Kip1 and p57Kip2, respectively, unlocking a transcriptional myogenic program, partly MYOD-dependent, resulting in de novo expression of terminal muscle differentiation markers. SKP2 depletion strongly affects stemness and tumorigenic features in vitro and prevents in vivo tumor growth. The in vitro effects are mirrored by the SKP2 inhibitor SMIP004. Moreover, the investigational NEDDylation inhibitor MLN4924 hampers SKP2 functions restraining FN-RMS cell survival and tumor growth. Our results uncover a MYOD-SKP2 axis crucial for the crosstalk between transcriptional and post-translational mechanisms that contribute to FN-RMS tumorigenesis and broaden the understanding of MYOD function. Furthermore, they suggest inhibition of NEDDylation as a potential therapeutic approach in this tumor.

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