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Analysis of gene expression changes in patient-derived gastric cancer cells after anticancer drug treatment or ALDH1A3 knockdown

ABSTRACT: Tumors consist of heterogeneous cell population, containing cancer cell subpopulations with anticancer drug-resistant property, called “persister” cells. To reveal the character of the persister cells, we analyzed gene expression profile of patient-derived gastric cells and residual cancer cells after treatment with 5-FU or SN38, an active metabolite of irinotecan. In our study, we identified ALDH1A3 as a marker and a cell proliferation factor of persister cells. To examine molecular pathways regulated by ALDH1A3, we analyzed gene expression profile of patient-derived gastric JSC15-3 in which ALDH1A3 was knocked down by using shRNAs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139331 | GEO | 2020/04/14

REPOSITORIES: GEO

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Pharmacological targeting of histone H3K27 acetylation/BRD4-dependent induction of ALDH1A3 for early-phase drug tolerance of gastric cancer

Project description:Drug-tolerant persister (DTP) cells arise in the early phase of chemotherapy and contribute to tumor relapse. In gastric cancer, we previously identified aldehyde dehydrogenase 1 family member A3 (ALDH1A3) as a DTP signature gene that contributes to survival after chemotherapy, while it remains elusive how the ALDH1A3-overexpressing DTP cells are enriched after chemotherapy and contribute to tumor promotion. Here, we demonstrated that ALDH1A3 was frequently overexpressed in clinical gastric cancer specimen after neoadjuvant chemotherapy and ALDH1A3 overexpression in gastric cancer patient-derived cells (PDCs) promoted tumor growth in vivo. Live imaging revealed that the ALDH1A3-overexpressing DTP cells were induced rather than selected after 5-fluorouracil (5-FU) treatment. We identified global elevation of histone H3 lysine 27 acetylation (H3K27ac) in the promoter regions of DTP cells including ALDH1A3 gene locus. Chemical screening further revealed bromodomain and extra-terminal motif (BET) protein inhibitors as efficient perturbators of the DTP phenotype. The BET inhibitors suppressed 5-FU-induced ADLH1A3 expression and selectively prevented the DTP cell proliferation. Importantly, ALDH1A3 downregulation and growth inhibition by BET inhibitors was rescued by exogenous ALDH1A3 expression. Among BET proteins, BRD4 was preferentially recruited to the ALDH1A3 promoter and promoted its expression in DTP cells. The BET inhibitor, Birabresib/OTX015, significantly suppressed ALDH1A3 expression and potentiated antitumor effect of 5-FU in gastric PDC xenograft model. These data indicate that the global H3K27ac induction and the BRD4-dependent ALDH1A3 induction is essential for gastric cancer drug tolerance.

2023-10-24 | GSE245888 | GEO

Pharmacological targeting of histone H3K27 acetylation/BRD4-dependent induction of ALDH1A3 for early-phase drug tolerance of gastric cancer

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ALDH1A3-mediated gene expression in MDA-MB-231 cells and MDA-MB-468 cells

Project description:To determine the effect ALDH1A3 expression on global gene expression in MDA-MB-231 cells and MDA-MB-468 cells In MDA-MB-231 cells, ALDH1A3 was overexperssed (have low endogenous levels of ALDH1A3) and compared to MSCV empty vector control. In MDA-MB-468 cells that have high endogenous levels of ALDH1A3, ALDH1A3 expresion was reduced with ALDH1A3 shRNA1 and compared to scramble shRNA control.

2014-02-04 | E-GEOD-49322 | biostudies-arrayexpress

KDM4C epigenetically regulates and forms a feed-forward loop with ALDH1A3 to maintain gastric cancer stemness

Project description:Gastric cancer (GC) stem cells (GCSCs) are characterized as high level of ALDH activity, however, the mechanisms of maintenance of high ALDH activity and stemness in GCSCs are largely unknown. Here, we report that KDM4C, a H3K9me2/3-demethylase, epigenetically regulates ALDH1A3 by histone demethylation and forms a feed-forward loop with ALDH1A3 to supports GS stemness. Ectopic expression of both KDM4C and ALDH1A3 promotes the properties of GCSCs, including spherogenecity, self-renewal, CD44 expression and ALDH activity; knockdown of anyone abolished the effect of each other. KDM4C directly binds to the promoter of ALDH1A3, leads to histone demethylation, thereby promoting ALDH1A3 transcription. Upregulated ALDH1A3 in turn transcriptionally upregulates KDM4C. Simultaneous inhibition of KDM4C and ALDH1A3 synergistically sensitizes GC sphere-derived cells to traditional chemotherapeutic drugs. The finding that upregulated ALDH1A3 promotes its own transcription via KDM4C-mediated epigenetic modification represents an important feed-forward mechanism for GCSCs to maintain stemness and promote tumourigenesis and our work thus suggests a novel therapeutic strategy for eradicating human GCSCs. To investigate the mechanisms underlying KDM4C promoting CG stemness, we identified the differentially expressed proteins (DEPs) between KDM4C-overexpressing and control AGS cells by iTRAQ-based quantitative proteomic analysis.

2022-02-16 | PXD023455 | Pride

Analysis of gene expression changes in patient-derived gastric cancer cells after anticancer drug treatment or ALDH1A3 knockdown

Project description:Analysis of gene expression changes in patient-derived gastric cancer cells after anticancer drug treatment or ALDH1A3 knockdown

| PRJNA579327 | ENA

Human breast cancer MCF-7 cells: SN38-selected cells

2012-03-01 | GSE27534 | GEO

Genetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure

Project description:Type 2 diabetes (T2D) is associated with defective insulin secretion, reduced β-cell mass, and β-cell dedifferentiation. Aldehyde dehydrogenase 1 isoform A3 (ALHD1A3) serves as a marker of β-cell dedifferentiation and correlates with T2D progression. ALDH1A3-positive β-cells (A+) demonstrate impaired insulin secretion, and their numbers decrease when diabetic mice are rendered euglycemic by pair-feeding. It is unknown whether ALDH1A3 activity contributes to β-cell failure, and whether the decrease of A+ cells under pair-feeding is due to β-cell restoration. To tackle these questions, we (i) investigated the fate of A+ cells during pair-feeding by lineage-tracing, (ii) somatically ablated ALDH1A3 in diabetic β-cells, and (iii) used a novel selective ALDH1A3 inhibitor to treat diabetes. Lineage tracing and functional characterization show that A+ cells can be reconverted to functional, mature β-cells. Genetic or pharmacological inhibition of ALDH1A3 in diabetic mice lowers glycemia and increases insulin secretion. Molecular interrogation of β-cells following ALDH1A3 inhibition show a reactivation of differentiation as well as regeneration pathways through the REG gene family. We conclude that ALDH1A3 inhibition offers a therapeutic strategy for β-cell dysfunction in diabetes.

2023-01-09 | GSE218047 | GEO

A specific inhibitor of ALDH1A3 regulates retinoic acid biosynthesis in glioma stem cells

Project description:Elevated aldehyde dehydrogenase (ALDH) activity correlates with poor outcome for many solid tumors as ALDHs potentially regulate cell proliferation and chemoresistance of cancer stem cells (CSCs). Accordingly, potent and selective inhibitors of key ALDHs may represent a novel CSC-directed treatment paradigm for ALDH+ cancer types. Of the many ALDH isoforms, we and others have implicated the elevated expression of ALDH1A3 in mesenchymal glioma stem cells (MES GSCs) as a target for the development of novel therapeutics. To this end, we used our structure of human ALDH1A3 combined with in silico modeling to identify a selective, active-site inhibitor of ALDH1A3. The lead compound, MCI-INI-3, is a selective competitive inhibitor of human ALDH1A3 and shows poor inhibitory effect on the structurally related isoform ALDH1A1. Mass spectrometry-based cellular thermal shift analysis revealed that ALDH1A3 is the primary binding protein for MCI-INI-3 in MES GSC lysates. The inhibitory effect of MCI-INI-3 on retinoic acid biosynthesis is comparable with that of ALDH1A3 knockout, suggesting that effective inhibition of ALDH1A3 is achieved with MCI-INI-3. Further development is warranted to characterize the role of ALDH1A3 and retinoic acid biosynthesis in glioma stem cell growth and differentiation.

2022-02-15 | PXD028125 | Pride

Expression data from glioma stem cells (GSC), comparing the WT cells to those after ALDH1A3-KO

Project description:Elevated aldehyde dehydrogenase (ALDH) activity correlates with poor outcome for many solid tumors as ALDHs potentially regulate cell proliferation and chemoresistance of cancer stem cells (CSCs). ALDH1A3 is the dominant isomer of the ALDH gene family in Mesenchymal subtype of GSC cells and is highly upregulated compared to other subtype of GSCs. ALDH1A3 is an important enzyme in the synthesis of Retinoic Acid, which regulates various downstream pathways and the transcription of numerous genes. Microarray analysis of the GSCs before or after depletion of ALDH1A3 provides important information to determine the genes regulated by ALDH1A3 in the mesenchymal subtype of GSCs. We used microarrays to analyze the transcriptome change after the depletion of ALDH1A3 in GSC-326 cells that express very high levels of ALDH1A3.

2021-10-07 | GSE185463 | GEO

Human breast cancer MCF-7 cells: SN38-selected cells

Project description:Transcriptional profiling of human breast cancer MCF-7 cells comparing control untreated cells with cells exposed to step-wise increasing doses of SN38, an active metabolite of irinotecan. MCF-7 cell clones were established by a limiting dilution method. SN38-sensitive MCF-7 clone (Clone 3) was used for further analyses. MCF-7/SNR cells were established by continuously exposing this clone to SN38 with stepwise increasing concentrations ranging from 0.5 ng/mL to 50 ng/mL over a period of six months. MCF-7/SNR cells were maintained in the presence of 50 ng/mL SN38 until 24 h prior to any experiment. Total RNA was extracted from MCF-7 and MCF-7/SNR cells for cDNA microarray analysis.

2012-03-01 | E-GEOD-27534 | biostudies-arrayexpress

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