PRMT5 silencing selectively affects <i>MTAP</i>‐deleted mesothelioma: In vitro evidence of a novel promising approach

Barbarino, Marcella; Cesari, D.; Bottaro, Maria; Luzzi, Luca; Namagerdi, Asadoor; Bertolino, Franca Maria; Bellan, Cristiana; Proietti, Fabrizio; Somma, Pasquale; Micheli, Mariacarolina; Santi, Maria Margherita De; Guazzo, Raffaella; Mutti, Luciano; Pirtoli, Luigi; Paladini, Piero; Indovina, Paola; Giordano, Antonio

doi:10.1111/jcmm.15213

Cited by 21 publications

(17 citation statements)

References 58 publications

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“…It should be noted that given the co-deletion of MTAP with CDKN2A, which has been also shown to be negatively prognostic, it was not possible to deconvolute the impact of MTAP in isolation from our data involving chromosome 9p21.3 deleted cel lines. PRMT5 plays a key role in the regulation of several pathways including DNA damage response, apoptosis, inhibition of tumour suppressors, and activation of survival pathways 10 and has been reported to be a dependency in MTAP negative cells 11 , which we have verified in MPM. We confirmed global epigenetic modification associated with reduced H4R3me2S and re-expression of tumour suppressors, such as EIF3F, FOXP4, ZBTB4, GANAB, TMEM141, in association with loss of clonogenicity.…”

Section: Discussionsupporting

confidence: 68%

Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression

Busacca

Zhang

Sharkey

et al. 2021

Sci Rep

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We hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM.

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Section: Discussionsupporting

confidence: 68%

Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression

Busacca

Zhang

Sharkey

et al. 2021

Sci Rep

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“…HMC7 cells were isolated from a patient with a bullous emphysema in a spontaneous pneumothorax. MMP1 and MMP2 mesothelioma cell lines were isolated from patients’ who underwent surgery at the Thoracic Surgery Unit (Siena, Italy) for decortication, without prior chemotherapy or radiotherapy [ 9 ]. All specimens were collected from patients diagnosed for pleural mesothelioma (MMP1: epithelioid; MMP2: biphasic) with their written consent.…”

Section: Methodsmentioning

confidence: 99%

Drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma

et al. 2020

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SummaryObjectives Malignant pleural mesothelioma (MPM) is an occupational disease mainly due to asbestos exposure. Effective therapies for MPM are lacking, making this tumour type a fatal disease. Materials and Methods In order to meet this need and in view of a future “drug repositioning” approach, here we screened five MPM (Mero-14, Mero-25, IST-Mes2, NCI-H28 and MSTO-211H) and one SV40-immortalized mesothelial cell line (MeT-5A) as a non-malignant model, with a library of 1170 FDA-approved drugs. Results Among several potential compounds, we found that fludarabine (F-araA) and, to a lesser extent, risedronic acid (RIS) were cytotoxic in MPM cells, in comparison to the non-malignant Met-5A cells. In particular, F-araA reduced the proliferation and the colony formation ability of the MPM malignant cells, in comparison to the non-malignant control cells, as demonstrated by proliferation and colony formation assays, in addition to measurement of the phospho-ERK/total-ERK ratio. We have shown that the response to F-araA was not dependent upon the expression of DCK and NT5E enzymes, nor upon their functional polymorphisms (rs11544786 and rs2295890, respectively). Conclusion This drug repositioning screening approach has identified that F-araA could be therapeutically active against MPM cells, in addition to other tumour types, by inhibiting STAT1 expression and nucleic acids synthesis. Further experiments are required to fully investigate this.

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“…50,51 Inhibition of protein arginine N-methyltransferase 5 (PRMT5) has recently emerged as a potential therapy against MTAPdeficient cancers. 52 MTA inhibits PRMT5 by competing with SAM for binding to the catalytic site. 50 Methionine restriction (MR) is sufficient for eliminating MTA accumulation to levels found in MTAP-expressing cells.…”

Section: The Physiological Role Of Methionine Metabolismmentioning

confidence: 99%

Methionine metabolism in chronic liver diseases: an update on molecular mechanism and therapeutic implication

Wang

Liang

et al. 2020

Sig Transduct Target Ther

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As one of the bicyclic metabolic pathways of one-carbon metabolism, methionine metabolism is the pivot linking the folate cycle to the transsulfuration pathway. In addition to being a precursor for glutathione synthesis, and the principal methyl donor for nucleic acid, phospholipid, histone, biogenic amine, and protein methylation, methionine metabolites can participate in polyamine synthesis. Methionine metabolism disorder can aggravate the damage in the pathological state of a disease. In the occurrence and development of chronic liver diseases (CLDs), changes in various components involved in methionine metabolism can affect the pathological state through various mechanisms. A methionine-deficient diet is commonly used for building CLD models. The conversion of key enzymes of methionine metabolism methionine adenosyltransferase (MAT) 1 A and MAT2A/MAT2B is closely related to fibrosis and hepatocellular carcinoma. In vivo and in vitro experiments have shown that by intervening related enzymes or downstream metabolites to interfere with methionine metabolism, the liver injuries could be reduced. Recently, methionine supplementation has gradually attracted the attention of many clinical researchers. Most researchers agree that adequate methionine supplementation can help reduce liver damage. Retrospective analysis of recently conducted relevant studies is of profound significance. This paper reviews the latest achievements related to methionine metabolism and CLD, from molecular mechanisms to clinical research, and provides some insights into the future direction of basic and clinical research.

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PRMT5 silencing selectively affects MTAP‐deleted mesothelioma: In vitro evidence of a novel promising approach

Cited by 21 publications

References 58 publications

Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression

Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression

Drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma

Methionine metabolism in chronic liver diseases: an update on molecular mechanism and therapeutic implication

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