Knock-Down of PRAME Increases Retinoic Acid Signaling and Cytotoxic Drug Sensitivity of Hodgkin Lymphoma Cells

Kewitz, Stefanie; Staege, Martin S.

doi:10.1371/journal.pone.0055897

Cited by 25 publications

(22 citation statements)

References 45 publications

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“…For instance, different expression levels of preferentially antigen expressed in melanoma (PRAME), a repressor of retinoic acid signaling, seem to affect ATRA sensitivity in cHL cell lines. 38 Our own findings obtained after derepressing treatment with the DNA-demethylating agent 5-Aza and the histone deacetylase inhibitor TSA support the idea that a master repressor of the B-cell program is selectively active in Hodgkin lymphoma, but epigenetically silenced in B-NHL and normal B cells. We may also have uncovered a putative role of the B-cell phenotype as a tumorsuppressive principle and novel vulnerability of cHL cells: different agents that led to the reexpression of B-cell-specific genes despite their pharmacologically distinct modes of action turned out to be toxic for cHL cells.…”

Section: Discussionsupporting

confidence: 59%

Pharmacological restoration and therapeutic targeting of the B-cell phenotype in classical Hodgkin lymphoma

Neuenschwander

et al. 2017

Blood

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Key Points• A pharmacological screening identified compounds that reactivate B-cell-specific gene expression in cHL cell lines.• B-cell phenotype-restoring drug combinations render cHL cell lines susceptible to B-NHL-reminiscent targeted therapies.Classical Hodgkin lymphoma (cHL), although originating from B cells, is characterized by the virtual lack of gene products whose expression constitutes the B-cell phenotype. Epigenetic repression of B-cell-specific genes via promoter hypermethylation and histone deacetylation as well as compromised expression of B-cell-committed transcription factors were previously reported to contribute to the lost B-cell phenotype in cHL. Restoring the B-cell phenotype may not only correct a central malignant property, but it may also render cHL susceptible to clinically established antibody therapies targeting B-cell surface receptors or small compounds interfering with B-cell receptor signaling. We conducted a high-throughput pharmacological screening based on >28 000 compounds in cHL cell lines carrying a CD19 reporter to identify drugs that promote reexpression of the B-cell phenotype. Three chemicals were retrieved that robustly enhanced CD19 transcription. Subsequent chromatin immunoprecipitation-based analyses indicated that action of 2 of these compounds was associated with lowered levels of the transcriptionally repressive lysine 9-trimethylated histone H3 mark at the CD19 promoter. Moreover, the antileukemia agents all-trans retinoic acid and arsenic trioxide (ATO) were found to reconstitute the silenced B-cell transcriptional program and reduce viability of cHL cell lines. When applied in combination with a screening-identified chemical, ATO evoked reexpression of the CD20 antigen, which could be further therapeutically exploited by enabling CD20 antibodymediated apoptosis of cHL cells. Furthermore, restoration of the B-cell phenotype also rendered cHL cells susceptible to the B-cell non-Hodgkin lymphoma-tailored small-compound inhibitors ibrutinib and idelalisib. In essence, we report here a conceptually novel, redifferentiation-based treatment strategy for cHL. (Blood. 2017;129(1):71-81)

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Section: Discussionsupporting

confidence: 59%

Pharmacological restoration and therapeutic targeting of the B-cell phenotype in classical Hodgkin lymphoma

Neuenschwander

et al. 2017

Blood

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“…Expression of PRAME serves as a poor prognostic marker in many cancers [18][19][20][21] . Consequently, the knockdown of PRAME is expected to be an interesting option for the development of new therapeutic strategies for cancer [22] . Since the clinical significance of PRAME expression in HCC is totally unknown, the aim of the current study was to clarify the significance of PRAME in HCC patients.…”

Section: Introductionmentioning

confidence: 99%

Impact of Preferentially Expressed Antigen of Melanoma on the Prognosis of Hepatocellular Carcinoma

Oyama

Kanki

Shimizu

et al. 2016

Gastrointest Tumors

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Background:Retinoids, vitamin A and its derivatives, have an antitumor effect on hepatocellular carcinoma (HCC). The function of retinoids is exerted by the complex of retinoic acid (RA) with the heterodimer of retinoid X receptor and the RA receptor. The preferentially expressed antigen of melanoma (PRAME) acts as a dominant repressor of RA signaling by binding to the complex. The significance of PRAME on the prognosis of HCC remains to be clarified. Methods: PRAME mRNA expression was examined by quantitative real-time polymerase chain reaction in both tumor and non-tumor tissues of 100 HCC patients who received surgical resection. The effect of PRAME knockdown on DR5-mediated RA transcriptional activity was examined. Results: In tumor tissues, there were significant associations among PRAME expression, clinical stage, tumor markers, and tumor numbers. In non-tumor tissues, there were significant associations among PRAME expression, overall survival, and disease-free survival. The knockdown of PRAME caused no reduction in DR5-mediated transcriptional activity of RA, suggesting that PRAME acts via other mechanisms than the DR5 RA-responsive elements. Conclusion: Our findings indicate that PRAME expression is a novel prognostic marker in HCC patients.

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“…Of interest, among the top genes highly expressed in SKOV-3 cells there is PRAME that in a wide variety of human malignancies correlates with poor clinical outcome [83]. It has been reported that PRAME proteins are associated to self-renewal cell maintenance [84] and are currently considered as potential target to hamper cancer cell proliferation [85]. …”

Section: Discussionmentioning

confidence: 99%

Candidate genes and pathways downstream of PAX8 involved in ovarian high-grade serous carcinoma

et al. 2016

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Understanding the biology and molecular pathogenesis of ovarian epithelial cancer (EOC) is key to developing improved diagnostic and prognostic indicators and effective therapies. Although research has traditionally focused on the hypothesis that high-grade serous carcinoma (HGSC) arises from the ovarian surface epithelium (OSE), recent studies suggest that additional sites of origin exist and a substantial proportion of cases may arise from precursor lesions located in the Fallopian tubal epithelium (FTE). In FTE cells, the transcription factor PAX8 is a marker of the secretory cell lineage and its expression is retained in 96% of EOC. We have recently reported that PAX8 is involved in the tumorigenic phenotype of ovarian cancer cells. In this study, to uncover genes and pathways downstream of PAX8 involved in ovarian carcinoma we have determined the molecular profiles of ovarian cancer cells and in parallel of Fallopian tube epithelial cells by means of a silencing approach followed by an RNA-seq analysis. Interestingly, we highlighted the involvement of pathways like WNT signaling, epithelial-mesenchymal transition, p53 and apoptosis. We believe that our analysis has led to the identification of candidate genes and pathways regulated by PAX8 that could be additional targets for the therapy of ovarian carcinoma.

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Knock-Down of PRAME Increases Retinoic Acid Signaling and Cytotoxic Drug Sensitivity of Hodgkin Lymphoma Cells

Cited by 25 publications

References 45 publications

Pharmacological restoration and therapeutic targeting of the B-cell phenotype in classical Hodgkin lymphoma

Pharmacological restoration and therapeutic targeting of the B-cell phenotype in classical Hodgkin lymphoma

Impact of Preferentially Expressed Antigen of Melanoma on the Prognosis of Hepatocellular Carcinoma

Candidate genes and pathways downstream of PAX8 involved in ovarian high-grade serous carcinoma

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