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Epigenetically Down-Regulated BRCA2 through Acetyltransferase KAT2B Increases the Sensitivity of Colorectal Cancer to Olaparib

ABSTRACT: The clinical application of anticancer drugs depends on preclinical models closely recapitulating the molecular profile. We report here the transcriptional profiles of HCT116 (colorectal cancer cells) treated with DMSO or Olaparib for 24 hours. For these two different treatments, also changes of molecule expression are available, which enables their stratification into drug-therapeuticly relevant molecule.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246781 | GEO | 2023/12/14

REPOSITORIES: GEO

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Epigenetically Down-Regulated BRCA2 through Acetyltransferase KAT2B Increases the Sensitivity of Colorectal Cancer to Olaparib

Project description:Epigenetically Down-Regulated BRCA2 through Acetyltransferase KAT2B Increases the Sensitivity of Colorectal Cancer to Olaparib

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Epigenetically Downregulated Breast Cancer Gene 2 through Acetyltransferase Lysine Acetyltransferase 2B Increases the Sensitivity of Colorectal Cancer to Olaparib.

Project description:Olaparib suppresses DNA damage repair by inhibiting the poly ADP ribose polymerase (PARP), especially in cancers with BRCA1/2 mutations or the BRCA-ness phenotype. However, the first trials showed that some patients with defective DNA damage repair are still resistant to olaparib. The recovery of the wildtype BRCA is a prominent mechanism of PARP inhibitor (PARPi) resistance in BRCA-deficient tumors, but additional molecular features of olaparib resistance remain poorly understood. The objective of our study was to find molecular parameters that contribute to olaparib response or resistance in CRC. We report that histone acetyltransferase KAT2B decreases BRCA2 expression by reducing the acetylation of the 27th amino acid in histone H3 (H3K27) at the promoter of the BRCA2 gene in colorectal cancer (CRC). This increases the sensitivity of CRC cells toward olaparib treatment. The H3K27ac binding domain of BRCA2 may be required for its transcription. Low endogenous KAT2B expression, which we identify in a subset of cultured BRCA2-expressing CRC cells, leads to an accumulation of γH2AX (more DNA damage), resulting in low PARPi resistance in BRCA-expressing cells. Our results reveal KAT2B and histone acetylation as regulators of BRCA2 expression and PARPi responses in BRCA2-expressing CRC cells, providing further insights into molecular prerequisites for targeting BRCA-functional tumors.

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Genome-wide analysis of enzalutamide- and/or olaparib-responsive gene expression in prostate cancer cells

Project description:Analysis of enzalutamide- and/or olaparib-responsive gene expression in prostate cancer cells. The hypothesis tested in the present study was that enzalutamide influences the expression of genes that are involved in important bioprocesses in prostate cance rcells, including DNA damage response genes and this effect may synergize with poly(ADP-ribose) polymerase inhibitor olaparib in cytotoxicity to prstate cancer cells. prostate cancer cells were pretreated with enzalutamide or vehicle control DMSO for 24 h, followed by treatment with enzalutamide, olaparib, enzalutamide+olaparib, or vehicle control DMSO for 48 h. Gene expression in enzalutamide+olaparib-treated cells was compared with taht in vehicle control- and single agent-treated cells.

2016-07-03 | E-GEOD-69249 | biostudies-arrayexpress

Activation of Wnt signaling promotes olaparib resistant ovarian cancer.

Project description:Sequencing of olaparib-resistant PEO1 derivatives (C4, C5, C10 and C18) and parental PEO1 (P1 and P2) cells was performed in order to determine mechanisms of acquired resistance in the resistant cell lines. PEO1 parental cell lines were authenticated prior to sequencing. PEO1 parental were confirmed to be BRCA2-mutated (5139C>G). Olaparib PEO1 resistant cells were generated through a step-wise escalation of olaparib (10nM to 8uM olaparib). In olaparib resistant lines an increase canonical Wnt signaling and loss of of non-canonical Wnt signaling was observed.

2018-07-28 | GSE117765 | GEO

Transcriptome profiling of Olaparib-resistant (OlapR) prostate cancer cell lines

Project description:Acquisition of resistance to the PARP inhibitor, Olaparib, constitutes a major challenge for the treatment of advanced prostate cancer. The purpose of this study was to identify molecular targets responsible for the development of acquired Olaparib resistance in advanced prostate cancer. Towards this goal, next-generation sequencing (NGS)-based gene expression profiling (RNA-Sequencing; RNA-Seq) was performed on castration-sensitive prostate cancer (CSPC)/Olaparib-sensitive LNCaP cells, castration-sensitive prostate cancer (CSPC)/Olaparib-resistant LN-OlapR cells, castration-resistant prostate cancer (CSPC)/Olaparib-sensitive C4-2B cells, and castration-resistant prostate cancer (CSPC)/Olaparib-resistant 2B-OlapR cells.

2023-12-06 | GSE249514 | GEO

Olaparib based photo-affinity probes for PARP-1 detection in living cells

Project description:The poly-ADP-ribose polymerase (PARP) is a protein from the family of ADP-ribosyltransferases that catalyzes poly adenosine diphosphate ribose (ADPR) formation in order to attract the DNA repair machinery to DNA damage sites. Inhibition of PARP activity by olaparib can cause cell death which is of clinical relevance in some tumor types. This demonstrates that quantification of PARP activity in the context of living cells is of great importance. In this work we present the design, synthesis and biological evaluation of photo-activatable affinity probes inspired by the olaparib molecule which are equipped with a diazirine for covalent attachment upon activation by UV light and a ligation handle for the addition of a reporter group of choice. SDS-PAGE, western blotting and label-free LC-MS/MS quantification analysis show that the probes target the PARP-1 protein and are selectively outcompeted by olaparib suggesting binding in the same enzymatic pocket.

2020-04-29 | PXD018661 | Pride

The effect of Olaparib or MNA on bone marrow derived macrophage gene expression during induction

Project description:To investigate the effect of olaparib or MNA on macrophage, we treated bone marrow with olaparib or MNA during BMDM induction for 6 days.

2022-08-05 | GSE210378 | GEO

Genome-wide CRISPR knockout screen using GeCKO v2 to identify synthetic lethal interactions with the PARP inhibitor Olaparib

Project description:In this study, a population of knockout cells was generated using the GeCKO v2 sgRNA library. The population of knockout cells was treated with the PARP inhibitor olaparib for 14 days. Over this time, knockout cells that were sensitive to olaparib treatment would die and a population of knockout cells that was resistant to olaparib treatment remained. Cells from olaparib and DMSO conditions and the sgRNA cassette in the knockout cells was amplified and sequenced to identify synthetic lethal or suppressor interactions with olaparib treatment.

2020-08-01 | GSE145743 | GEO

Epigenetically Down-Regulated Acetyltransferase PCAF Increases the Resistance of Colorectal Cancer to 5-Fluorouracil.

Project description:Only 10%-20% of colorectal cancer (CRC) patients observe effective responses to 5-fluorouracil (5-FU) based chemo-treatment. We used real-time PCR array and Western blot analysis to examine the expression alteration of acetyltransferases and deacetylases in 5-FU resistant CRC cell lines as compared to their respective parental CRC cell lines. Unlike other acetyltransferases and deacetylases, we found that the expression of acetyltransferase P300/CBP-associated factor (PCAF) is consistently decreased in three 5-FU resistant CRC cell lines. Similarly, knockdown of PCAF in HCT116 CRC parental cell line also increases the resistance to 5-FU and attenuates 5-FU-induced apoptosis. Mechanistically, we demonstrated that increased binding of trimethylated histone H3K27 in the promoter region of PCAF attenuated its transcription in 5-FU resistant HCT116/5-FU cells. Decreased PCAF impairs the acetylation of p53 and attenuates the p53-dependent transcription of p21, which results in the increased cyclin D1 and phosphorylation of Retinoblastoma 1. Conversely, overexpression of PCAF in CRC cell lines increases p21 and their susceptibility to 5-FU in vitro and in vivo. However, knockdown of p21 abolishes the beneficial effects of PCAF overexpression on increasing the sensitivity of HCT116/5-FU cells to 5-FU. Also, the reduced intensity of PCAF immunostaining was observed in the precancerous lesion, and microarray data from the public database further demonstrated the association between PCAF down-regulation and poor survival outcome. Our data suggest that PCAF-mediated p53 acetylation is an essential regulatory mechanism for increasing the susceptibility of CRC to 5-FU.

| S-EPMC6488821 | biostudies-literature

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