PTPRM methylation induced by FN1 promotes the development of glioblastoma by activating STAT3 signalling.

The phosphorylation of signal transducer and activator of transcription protein 3 (STAT3) is up-regulated in glioblastoma (GBM) cells and is regulated by protein tyrosine phosphatase receptor type M (PTPRM). Fibronectin-1 (FN1) is also reported to be up-regulated in GBM. We explored the role of FN1-induced PTPRM methylation in GBM. The lentivirus particles of oe-PTPRM, sh-PTPRM, oe-FN1, sh-FN1, or their negative controls (NSCs) were transfected into GBM cells with or without stattic (0.5 μM, 24 h) or 5-aza (1 μM, 0, 2, 4 h) treatments. Methylation-specific PCR was performed to detect PTPRM methylation levels. PTPRM was down-regulated (0.373 ± 0.124- and 0.455 ± 0.109-fold), FN1 and p-STAT3 were up-regulated (p < 0.001) in A172 and U87 MG cells as compared to NSCs. Overexpressing PTPRM inhibited STAT3 phosphorylation. Interfering with PTPRM increased colony numbers in A172 and U-87 MG cells (2.253 ± 0.111- and 2.043 ± 0.19-fold), and stattic reduced them. Cell viability was reduced after treatment with 5-aza in A172 and U-87 MG cells (p < 0.05). P-STAT3 was down-regulated after 5-aza treatment. Overexpressing FN1 decreased PTPRM levels (p < 0.001), knockdown of FN1 decreased PTPRM methylation and inhibited STAT3 phosphorylation. Overexpressing FN1 increased cell viability (1.497 ± 0.114- and 1.460 ± 0.151-fold), and stattic or 5-aza reversed such effects (p < 0.05). The up-regulation of FN1 reduced PTPRM by increasing its methylation, resulting in an increase of STAT3 phosphorylation and promoting GBM cell proliferation. Interfering with FN1 may be a potential therapeutic target for GBM.

Citation

Jian Song, Di Zhao, Guozhu Sun, Jiankai Yang, Zhongqiang Lv, Baohua Jiao. PTPRM methylation induced by FN1 promotes the development of glioblastoma by activating STAT3 signalling. Pharmaceutical biology. 2021 Dec;59(1):904-911

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PMID: 34225581

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