The importance of methylthioadenosine phosphorylase deficiency in human malignancy

AbstractWe 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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Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine

Nature Communications ◽

10.1038/s41467-021-24240-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yasaman Barekatain ◽

Jeffrey J. Ackroyd ◽

Victoria C. Yan ◽

Sunada Khadka ◽

Lin Wang ◽

...

Keyword(s):

Clinical Relevance ◽

Homozygous Deletion ◽

In Vitro Models ◽

Arginine Methyltransferase ◽

Human Glioblastoma ◽

Primary Glioblastoma ◽

Methylthioadenosine Phosphorylase ◽

Metabolomic Profiling

AbstractHomozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP-deleted cell lines in culture show elevation of MTAP’s substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated in vitro, the clinical relevance relies on exhibiting significant MTA accumulation in human glioblastoma. In this work, using comprehensive metabolomic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of extracellular MTA. We further demonstrate that homozygous MTAP-deleted primary glioblastoma tumors do not significantly accumulate MTA in vivo due to metabolism of MTA by MTAP-expressing stroma. These findings highlight metabolic discrepancies between in vitro models and primary human tumors that must be considered when developing strategies for precision therapies targeting glioblastoma with homozygous MTAP deletion.

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Biochemical genetic analysis of the role of methylthioadenosine phosphorylase in a murine lymphoid cell line.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)32175-6 ◽

1983 ◽

Vol 258 (12) ◽

pp. 7288-7291

Author(s):

M Kubota ◽

N Kamatani ◽

D A Carson

Keyword(s):

Genetic Analysis ◽

Cell Line ◽

Lymphoid Cell ◽

Lymphoid Cell Line ◽

Methylthioadenosine Phosphorylase ◽

Biochemical Genetic

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Loss of 5′-Methylthioadenosine Phosphorylase (MTAP) is Frequent in High-Grade Gliomas; Nevertheless, it is Not Associated with Higher Tumor Aggressiveness

Cells ◽

10.3390/cells9020492 ◽

2020 ◽

Vol 9 (2) ◽

pp. 492 ◽

Cited By ~ 1

Author(s):

Weder Pereira de Menezes ◽

Viviane Aline Oliveira Silva ◽

Izabela Natália Faria Gomes ◽

Marcela Nunes Rosa ◽

Maria Luisa Corcoll Spina ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Lines ◽

In Silico ◽

Glioma Cell ◽

Clinicopathological Features ◽

Migration And Invasion ◽

High Grade ◽

Methylthioadenosine Phosphorylase ◽

Frequent Event ◽

High Grade Gliomas

The 5’-methylthioadenosine phosphorylase (MTAP) gene is located in the chromosomal region 9p21. MTAP deletion is a frequent event in a wide variety of human cancers; however, its biological role in tumorigenesis remains unclear. The purpose of this study was to characterize the MTAP expression profile in a series of gliomas and to associate it with patients’ clinicopathological features. Moreover, we sought to evaluate, through glioma gene-edited cell lines, the biological impact of MTAP in gliomas. MTAP expression was evaluated in 507 glioma patients by immunohistochemistry (IHC), and the expression levels were associated with patients’ clinicopathological features. Furthermore, an in silico study was undertaken using genomic databases totalizing 350 samples. In glioma cell lines, MTAP was edited, and following MTAP overexpression and knockout (KO), a transcriptome analysis was performed by NanoString Pan-Cancer Pathways panel. Moreover, MTAP’s role in glioma cell proliferation, migration, and invasion was evaluated. Homozygous deletion of 9p21 locus was associated with a reduction of MTAP mRNA expression in the TCGA (The Cancer Genome Atlas) - glioblastoma dataset (p < 0.01). In addition, the loss of MTAP expression was markedly high in high-grade gliomas (46.6% of cases) determined by IHC and Western blotting (40% of evaluated cell lines). Reduced MTAP expression was associated with a better prognostic in the adult glioblastoma dataset (p < 0.001). Nine genes associated with five pathways were differentially expressed in MTAP-knockout (KO) cells, with six upregulated and three downregulated in MTAP. Analysis of cell proliferation, migration, and invasion did not show any significant differences between MTAP gene-edited and control cells. Our results integrating data from patients as well as in silico and in vitro models provide evidence towards the lack of strong biological importance of MTAP in gliomas. Despite the frequent loss of MTAP, it seems not to have a clinical impact in survival and does not act as a canonic tumor suppressor gene in gliomas.

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