Dataset Information

Development of novel chemical inhibitors of SETD8

ABSTRACT: SETD8 is a histone methyltransferase that catalyzes the monomethylation of histone H4K20. Overexpressed in cancer, several studies have suggested that it could be a potential target for treatment in certain tumors. However, there are currently very few SETD8 inhibitors, and all of them have bad pharmacological properties. Based on previously published structures of SETD8 bound to an H4K20me peptide, we have discovered a new chemical series of SETD8 inhibitors. As part of the characterization of these molecules, we conducted Thermal Proteome Profiling, aiming to discover potential additional targets as well as a better understanding of the signaling pathways that are affected by the drug.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): U2-os Cell, Epithelial Cell

DISEASE(S): Osteosarcoma

SUBMITTER: Rozbeh Jafari

LAB HEAD: Rozbeh Jafari

PROVIDER: PXD051199 | Pride | 2024-10-17

REPOSITORIES: Pride

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Source:

			Action	DRS
	HFLe_RJ1705A_RJOFJC_20170701_250ug_23R2_IPG3-10_fr01.raw	Raw
	HFLe_RJ1705A_RJOFJC_20170701_250ug_23R2_IPG3-10_fr02.raw	Raw
	HFLe_RJ1705A_RJOFJC_20170701_250ug_23R2_IPG3-10_fr03.raw	Raw
	HFLe_RJ1705A_RJOFJC_20170701_250ug_23R2_IPG3-10_fr04.raw	Raw
	HFLe_RJ1705A_RJOFJC_20170701_250ug_23R2_IPG3-10_fr05.raw	Raw

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Publications

SETD8 inhibition targets cancer cells with increased rates of ribosome biogenesis.

Murga Matilde M Lopez-Pernas Gema G Soliva Robert R Fueyo-Marcos Elena E Amor Corina C Faustino Ignacio I Serna Marina M Serrano Alicia G AG Díaz Lucía L Martínez Sonia S Blanco-Aparicio Carmen C Antón Marta Elena ME Seashore-Ludlow Brinton B Pastor Joaquín J Jafari Rozbeh R Lafarga Miguel M Llorca Oscar O Orozco Modesto M Fernández-Capetillo Oscar O

Cell death & disease 20240928 9

SETD8 is a methyltransferase that is overexpressed in several cancers, which monomethylates H4K20 as well as other non-histone targets such as PCNA or p53. We here report novel SETD8 inhibitors, which were discovered while trying to identify chemicals that prevent 53BP1 foci formation, an event mediated by H4K20 methylation. Consistent with previous reports, SETD8 inhibitors induce p53 expression, although they are equally toxic for p53 proficient or deficient cells. Thermal stability proteomics ...[more]

PMID: 39341827

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Project description:Background:; Osteoblast differentiation requires the coordinated stepwise expression of multiple genes. Histone deacetylase inhibitors (HDIs) accelerate the osteoblast differentiation process by blocking the activity of histone deacetylases (HDACs), which alter gene expression by modifying chromatin structure. We previously demonstrated that HDIs and HDAC3 shRNAs accelerate matrix mineralization and the expression of osteoblast maturation genes (e.g. alkaline phosphatase, osteocalcin). Identifying other genes that are differentially regulated by HDIs might identify new pathways that contribute to osteoblast differentiation. Results:; To identify other osteoblast genes that are altered early by HDIs, we incubated MC3T3-E1 preosteoblasts with HDIs (trichostatin A, MS-275, or valproic acid) for 18 hours in osteogenic conditions. The promotion of osteoblast differentiation by HDIs in this experiment was confirmed by osteogenic assays. Gene expression profiles relative to vehicle-treated cells were assessed by microarray analysis with Affymetrix GeneChip 430 2.0 arrays. The regulation of several genes by HDIs in MC3T3-E1 cells and primary osteoblasts was verified by quantitative real-time PCR. Nine genes were differentially regulated by at least two-fold after exposure to each of the three HDIs and six were verified by PCR in osteoblasts. Four of the verified genes (solute carrier family 9 isoform 3 regulator 1 (Slc9a3r1), sorbitol dehydrogenase 1, a kinase anchor protein, and glutathione S-transferase alpha 4) were induced. Two genes (proteasome subunit, beta type 10 and adaptor-related protein complex AP-4 sigma 1) were suppressed. We also identified eight growth factors and growth factor receptor genes that are significantly altered by each of the HDIs, including Frizzled related proteins 1 and 4, which modulate the Wnt signaling pathway. Conclusions: This study identifies osteoblast genes that are regulated early by HDIs and indicates pathways that might promote osteoblast maturation following HDI exposure. One gene whose upregulation following HDI treatment is consistent with this notion is Slc9a3r1. Also known as NHERF1, Slc9a3r1 is required for optimal bone density. Similarly, the regulation of Wnt receptor genes indicates that this crucial pathway in osteoblast development is also affected by HDIs. These data support the hypothesis that HDIs regulate the expression of genes that promote osteoblast differentiation and maturation. Experiment Overall Design: To identify other osteoblast genes that are altered early by HDIs, we incubated MC3T3-E1 preosteoblasts with HDIs (trichostatin A, MS-275, or valproic acid) or the vehicle control (DMSO) for 18 hours in osteogenic conditions. Gene expression profiles relative to vehicle-treated cells were assessed in triplicate (in some cases quadruplicate) samples by microarray analysis with Affymetrix GeneChip 430 2.0 arrays.