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Oncogenic role of SOX9-DHCR24-cholesterol biosynthesis axis in IGH-BCL2 positive diffuse large B-cell lymphomas [RNA-seq]

ABSTRACT: Although oncogenicity of the stem cell regulator SOX9 has been implicated in many solid tumors, its role in lymphomagenesis remains largely unknown. In this study, we showed that SOX9 is overexpressed preferentially in a subset of diffuse large B-cell lymphomas (DLBCL) harboring IGH-BCL2 translocations. SOX9 positivity in DLBCL correlates with advanced stage of disease. Silencing of SOX9 decreased cell proliferation, induced G1/S arrest and increased apoptosis of DLBCL cells, both in vitro and in vivo. Whole transcriptome analysis and CHIP-seq assays identified DHCR24, a terminal enzyme in cholesterol biosynthesis, as a direct target of SOX9, which promotes cholesterol synthesis by increasing DHCR24 expression. Enforced expression of DHCR24 was capable of rescuing the phenotypes associated with SOX9 knockdown in DLBCL cells. In DLBCL cell line xenograft models, SOX9 knockdown resulted in lower DHCR24 level, reduced cholesterol content and decreased tumor load. Pharmacological inhibition of cholesterol synthesis also inhibited DLBCL xenograft tumorigenesis, the reduction of which is more pronounced in DLBCL cell line with higher SOX9 expression, suggesting that it may be addicted to cholesterol. In summary, our study demonstrates that SOX9 can drive lymphomagenesis through DHCR24 and the cholesterol biosynthesis pathway. This SOX9-DHCR24-cholesterol 3 biosynthesis axis may serve as a novel treatment target for DLBCL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180051 | GEO | 2022/01/12

REPOSITORIES: GEO

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Oncogenic role of SOX9-DHCR24-cholesterol biosynthesis axis in IGH-BCL2 positive diffuse large B-cell lymphomas

Project description:Although oncogenicity of the stem cell regulator SOX9 has been implicated in many solid tumors, its role in lymphomagenesis remains largely unknown. In this study, we showed that SOX9 is overexpressed preferentially in a subset of diffuse large B-cell lymphomas (DLBCL) harboring IGH-BCL2 translocations. SOX9 positivity in DLBCL correlates with advanced stage of disease. Silencing of SOX9 decreased cell proliferation, induced G1/S arrest and increased apoptosis of DLBCL cells, both in vitro and in vivo. Whole transcriptome analysis and CHIP-seq assays identified DHCR24, a terminal enzyme in cholesterol biosynthesis, as a direct target of SOX9, which promotes cholesterol synthesis by increasing DHCR24 expression. Enforced expression of DHCR24 was capable of rescuing the phenotypes associated with SOX9 knockdown in DLBCL cells. In DLBCL cell line xenograft models, SOX9 knockdown resulted in lower DHCR24 level, reduced cholesterol content and decreased tumor load. Pharmacological inhibition of cholesterol synthesis also inhibited DLBCL xenograft tumorigenesis, the reduction of which is more pronounced in DLBCL cell line with higher SOX9 expression, suggesting that it may be addicted to cholesterol. In summary, our study demonstrates that SOX9 can drive lymphomagenesis through DHCR24 and the cholesterol biosynthesis pathway. This SOX9-DHCR24-cholesterol 3 biosynthesis axis may serve as a novel treatment target for DLBCL.

2022-01-12 | GSE179960 | GEO

IRF4 contributes to chemoresistance in IGH-BCL2 positive diffuse large B-cell lymphomas by mediating BCL2 induced SOX9 expression

Project description:SOX9 was identified as a prognostic biomarker particularly in IGH-BCL2 translocated germinal center B cell (GCB) subtypes of the diffuse large B cell lymphoma (DLBCL) and plays a vital role in lymphomagenesis. However, the molecular mechanism that modulating the aberrant expression of SOX9 in this DLBCL subset remains unknown. We have demonstrated that SOX9 enhanced IGH-BCL2 positive DLBCL subset resistance to either chemotherapy or BCL2 inhibitor. Moreover, we found that inhibition of BCL2 downregulates SOX9 in IGH-BCL2 positive DLBCL subset. We further identified that IRF4 is a key regulator to mediate BCL2 induced SOX9 expression, alongside with the chip-seq confirmed that IRF4 is a key transcription factor for SOX9 in DLBCL. In addition, BCL2 promote IRF4 entry into the nucleus by enhancing its protein stability, via downregulating of proteosome ubiquitination process, and, therefore, enforce SOX9-mediated phenotypes. Finally, we showed in DLBCL cell lines and xenografted mice model that in vivo inhibition of IRF4 with hIRF4 antisense oligonucleotide (ASO) repressed lymphomagenesis and DLBCL chemoresistance. Altogether, our data support the conclusion that IRF4 plays an essential role in BCL2 induced upregulation of SOX9 expression, and targeting IRF4 may represent a promising therapeutic strategy to cure relapse and refractory DLBCL in the future.

2024-09-30 | GSE278092 | GEO

Oncogenic role of SOX9-DHCR24-cholesterol biosynthesis axis in IGH-BCL2 positive diffuse large B-cell lymphomas

Project description:Oncogenic role of SOX9-DHCR24-cholesterol biosynthesis axis in IGH-BCL2 positive diffuse large B-cell lymphomas

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2020-12-17 | GSE156274 | GEO

Impact of liver-specific deletion of Dhcr24 gene on tissue gene expression

Project description:Genetic loss of the enzyme 3ß-hydroxysterol-∆24 reductase (DHCR24) results in Desmosterolosis (MIM #602398), a rare disease that presents with multiple congenital anomalies. Earlier studies to create a Dhcr24 global knockout mouse have failed as the pups died within 24 h of birth from lethal dermopathy. We generated a conditional knockout mouse model (Dhcr24flx/flx) and validated it by creating a liver-specific knockout Dhcr24flx/flx, Alb-Cre mouse using a mouse expressing cre recombinase driven by the albumin promoter. Despite increased circulatory and liver desmosterol due to loss of cholesterol synthesis in the liver, these mice demonstrated no marked changes in growth, fertility, hepatic architecture, lipoprotein secretion, etc. RNA-Seq analysis of the female mouse liver revealed no notable perturbations in pathways participating in cholesterol biosynthesis.

2020-09-04 | GSE146524 | GEO

Oncogenic role of SOX9-DHCR24-cholesterol biosynthesis axis in IGH-BCL2 positive diffuse large B-cell lymphomas [RNA-seq]

Project description:Oncogenic role of SOX9-DHCR24-cholesterol biosynthesis axis in IGH-BCL2 positive diffuse large B-cell lymphomas [RNA-seq]

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Expression of genes in HepG2 cells with Knock-out in cholesterol synthesis

Project description:HepG2 cell line CRISPR-Cas9 generated Knock-out in 4 cholesterol synthesis gene: CYP51, DHCR24, SC5D and HSD17B7 Excess of cholesterol associates with a variety of diseases so its synthesis must be under tight homeostatic control. The early part of cholesterol synthesis with rate-limiting HMGCR and SQLE steps is proceeded by the sterol part where numerous non-polar sterols with poorly defined biological functions are produced. To illuminate their role we developed knockouts (KO) for the consecutive enzymes that metabolize sterols towards cholesterol CYP51A1, DHCR24, SC5D resulted in the accumulation of specific set of sterols in each KO cell. Despite that, we targeted three steps of the cholesterol synthesis housekeeping pathway, the overlap of de-regulated genes was only 9%, suggesting that each set of sterols modulated the hepatic cell transcriptome uniquely. Lanosterol and 24,25-dihydrolanosterol, but not other non-polar sterols, provoked higher cell proliferation, cell cycle changes, and upregulation of metabolic pathways and transcription factors (TFs) associated with cancer progression and immune response like NFKB, SMAD, ESR1 and highly elevated LEF1 a protein from WNT signalling. In contrast, lathosterol and desmosterol caused slower proliferation and apoptosis promotion, through TFs like HNF1A and E2F. We were able to show how sterols from early part of synthesis can promote cell proliferation as sterols from end of synthesis suppress proliferation. These findings challenge the current dogma that sterols produced during cholesterol synthesis have similar biological functions

2024-08-08 | GSE221582 | GEO

Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model

Project description:Ferroptosis is a form of regulated cell death that can be induced by inhibition of the cystine-glutamate antiporter, system xc-. Among the existing system xc- inhibitors, imidazole ketone erastin (IKE) is a potent, metabolically stable inhibitor of system xc- and inducer of ferroptosis potentially suitable for in vivo applications. We investigated the pharmacokinetic and pharmacodynamic features of IKE in a diffuse large B cell lymphoma (DLBCL) xenograft model and demonstrated that IKE exerted an antitumor effect by inhibiting system xc-, leading to glutathione depletion, lipid peroxidation, and the induction of ferroptosis biomarkers both in vitro and in vivo. Using untargeted lipidomics and qPCR, we identified distinct features of lipid metabolism in IKE-induced ferroptosis. In addition, biodegradable polyethylene glycol-poly(lactic-co-glycolic acid) nanoparticles were employed to aid in IKE delivery and exhibited reduced toxicity compared with free IKE in a DLBCL xenograft model.

2019-04-17 | MTBLS774 | MetaboLights

Estrus Synchronization and Ovarian Hyper Stimulation Treatments Have Negligible Effects on Cumulus Oocyte Complexes Gene Expression: Induction of Ovulation Causes Major Expression Changes

Project description:The effects of exogenous hormones used for estrus synchronization, and ovarian hyper stimulation on cumulus oocyte complexes (COCs) gene expression in sexually mature rats were determined using microarrays. Gene expression in COCs collected from GnRH (Gtrt), GnRH+eCG (G+Etrt), and GnRH+eCG+hCG (G+E+Htrt) treatments were compared to COCs from naturally cycling (NC) rats. There was no significant difference in gene expression among NC, Gtrt and G+Etrt. Over 2600 genes were significantly different between NC and G+E+Htrt (P<0.05). Genes encoding proteins that are involved in prostaglandin synthesis (Ptgs2, Pla2g4a, Runx1); cholesterol biosynthesis (Hmgcr, Sc4mol, Dhcr24); receptors that allow cholesterol uptake (Ldlr, Scarb1); regulate progesterone synthesis (Star); inactivate estrogen (Sult1e1); and downstream effectors of LH signal (Pgr, Cebpb, Creb3l1, Areg, Ereg, Adamts1) were upregulated in G+E+Htrt. Genes encoding proteins that are involved in DNA replication (Ccne2, Orc5l, Rad50, Mcm6); reproductive developmental process and granulosa cell expansion (Gdf9, Bmp15, Amh, Amhr2, Bmpr1b, Tgfb2, Foxl2, Pde3a, Esr2, Fshr, Ybx2, Ccnd2, Ccnb1ip1, Zp3); maternal effect genes that are important for embryo development (Zar1, Npm2, Nlrp5, Dnmt1, H1foo, Zfp57); amino acid degradation and ketogenesis (Hmgcs2 , Cpt1b) were downregulated in G+E+Htrt. These results on rat model show that hormones used for estrus synchronization (Gtrt) and ovarian hyper stimulation (G+Etrt) had minimal effects on gene expression. However, induction of ovulation (G+E+Htrt) caused major changes in gene expression of rat COCs. This study provides comprehensive information about regulated genes during late follicle development and ovulation induction. Four experimental groups were used and there were 6 animals in each group. Total of 24 arrays were used. Only raw data used in publication.

2013-02-01 | E-GEOD-41836 | biostudies-arrayexpress

Increased cholesterol biosynthesis identified as a key feature and a therapeutic target of cancer stem cells as revealed by proteomic comparison of clinical breast cancer tissue and corresponding patient-derived xenografts and mammospheres

Project description:Cancer stem cells (CSCs) comprise a small subpopulation of undifferentiated cancer cells with the ability to self-renew and give rise to the heterogeneous cancer cell lineages that form tumorous masses. Thus, tumor eradication may be greatly improved by specifically targeting CSCs, as they exhibit resistance to conventional therapy. To gain insight into the unique biology of CSCs, we developed patient-derived xenograft (PDX) tumors from ER-negative breast cancer patient tissue from which we isolated mammospheres, a method known to enrich for cells with CSC-properties. An unbiased, comparative global proteomic analysis using label-free mass spectrometry was performed on the patient tumor tissues and corresponding PDX tumors and mammospheres. Good concordance between the proteome profiles of patient tumor tissue and corresponding PDX tumors was observed. However, lower abundance of immune- and extracellular matrix-related proteins and higher abundance of proteins associated with cell-to-cell adhesion including desmosome proteins and β-catenin were observed in PDX versus patient tumors. Interestingly, analysis of proteins elevated in mammospheres vs. PDX tumors identified an enrichment of proteins associated with de novo cholesterol synthesis. The clinical relevance of increased cholesterol biosynthesis protein expression was verified in a large gene expression data set of clinical breast cancers showing correlation with shorter relapse-free survival. RNA interference and chemical inhibition of the cholesterol biosynthesis pathway reduced mammosphere formation and growth of CSCs derived from PDX tumors and cancer cell lines. Our findings identify the cholesterol biosynthesis pathway as central for CSC growth and a potential therapeutic target for CSC as well as providing an additional mechanistic explanation for the observed benefit of statins in breast cancer treatment.

2019-07-02 | PXD011222 | Pride

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