PRMT6 activates cyclin D1 expression in conjunction with the transcription factor LEF1

Schneider, Lucas; Herkt, Stefanie; Wang, Lei; Feld, Ch.; Wesely, Josephine; Kuvardina, Olga N.; Meyer, Annekarin; Oellerich, Thomas; Häupl, Björn; Seifried, Erhard; Bönig, Halvard; Lausen, Joern

doi:10.1038/s41389-021-00332-z

“…Further, we performed a functional enrichment analysis of genes closely related to PRMT6 expression in GBM in the TCGA database and found that cell cycle was the function most closely related to PRMT6. PRMT6 regulation of the cell cycle of tumor cells has been reported in previous studies [41,42], and we also verified cell cycle is arrested at G0/G1 phase after PRMT6 silencing in GBM cells. In addition, we examined the expression of key cell cycle regulatory molecules in the G0/G1 phase.…”

Section: Discussionsupporting

confidence: 89%

PRMT6-CDC20 facilitates glioblastoma progression via the degradation of CDKN1B

Wang

¹

,

Xiao

²

,

Wu

³

et al. 2023

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PRMT6, a type I arginine methyltransferase, di-methylates the arginine residues of both histones and non-histones asymmetrically. Increasing evidence indicates that PRMT6 plays a tumor mediator involved in human malignancies. Here, we aim to uncover the essential role and underlying mechanisms of PRMT6 in promoting glioblastoma (GBM) proliferation. Investigation of PRMT6 expression in glioma tissues demonstrated that PRMT6 is overexpressed, and elevated expression of PRMT6 is negatively correlated with poor prognosis in glioma/GBM patients. Silencing PRMT6 inhibited GBM cell proliferation and induced cell cycle arrest at the G0/G1 phase, while overexpressing PRMT6 had opposite results. Further, we found that PRMT6 attenuates the protein stability of CDKN1B by promoting its degradation. Subsequent mechanistic investigations showed that PRMT6 maintains the transcription of CDC20 by activating histone methylation mark (H3R2me2a), and CDC20 interacts with and destabilizes CDKN1B. Rescue experimental results confirmed that PRMT6 promotes the ubiquitinated degradation of CDKN1B and cell proliferation via CDC20. We also verified that the PRMT6 inhibitor (EPZ020411) could attenuate the proliferative effect of GBM cells. Our findings illustrate that PRMT6, an epigenetic mediator, promotes CDC20 transcription via H3R2me2a to mediate the degradation of CDKN1B to facilitate GBM progression. Targeting PRMT6-CDC20-CDKN1B axis might be a promising therapeutic strategy for GBM.

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“…Further, we performed a functional enrichment analysis of genes closely related to PRMT6 expression in GBM in the TCGA database and found that cell cycle was the function most closely related to PRMT6. PRMT6 regulation of the cell cycle of tumor cells has been reported in previous studies [41,42], and we also veri ed cell cycle is arrested at G0/G1 phase after PRMT6 silencing in GBM cells. In addition, we examined the expression of key cell cycle regulatory molecules in the GO/G1 phase.…”

Section: Discussionsupporting

confidence: 77%

PRMT6-CDC20 facilitates glioblastoma progression via the degradation of CDKN1B

Wang¹,

Wang²,

Xiao³

et al. 2022

Preprint

0

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PRMT6, a type I arginine methyltransferase, di-methylates the arginine residues of both histones and non-histones asymmetrically. Increasing evidence indicates that PRMT6 plays a tumor mediator involved in human malignancies. Here, we aim to uncover the essential role and underlying mechanisms of PRMT6 in promoting glioblastoma (GBM) proliferation. Investigation of PRMT6 expression in glioma tissues demonstrated that PRMT6 is overexpressed, and elevated expression of PRMT6 is negatively correlated with poor prognosis in glioma/GBM patients. Silencing PRMT6 inhibited GBM cell proliferation and induced cell cycle arrest at the G0/G1 phase, while overexpressing PRMT6 had opposite results. Further, we found that PRMT6 attenuates the protein stability of CDKN1B by promoting its degradation. Subsequent mechanistic investigations showed that PRMT6 maintains the transcription of CDC20 by activating histone methylation mark (H3R2me2a), and CDC20 interacts with and destabilizes CDKN1B. Rescue experimental results confirmed that PRMT6 promotes the ubiquitinated degradation of CDKN1B and cell proliferation via CDC20. We also verified that the PRMT6 inhibitor (EPZ020411) could attenuate the proliferative effect of GBM cells. Our findings illustrate that PRMT6, an epigenetic mediator, promotes CDC20 transcription via H3R2me2a to mediate the degradation of CDKN1B to facilitate GBM progression. Targeting PRMT6-CDC20-CDKN1B axis might be a promising therapeutic strategy for GBM.

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“…The knockdown of PRMT6 in erythroleukemic cells resulted in a significantly decreased proliferation and an increase in cells in the G1 phase of the cell cycle due to a reduced Cyclin D1 expression. In normal leukemic cells, LEF1 (lymphoid enhancer-binding factor-1) interacts with PRMT6, provoking its recruitment at the Cyclin D1 promoter [ 87 ].…”

Section: Involvement Of Prmts In Hematopoiesis and Hematological Mali...mentioning

confidence: 99%

Protein Arginine Methyltransferases as Therapeutic Targets in Hematological Malignancies

Sauter

¹

,

Simonet

²

,

Guidez

³

et al. 2022

Cancers

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Arginine methylation is a common post-translational modification affecting protein activity and the transcription of target genes when methylation occurs on histone tails. There are nine protein arginine methyltransferases (PRMTs) in mammals, divided into subgroups depending on the methylation they form on a molecule of arginine. During the formation and maturation of the different types of blood cells, PRMTs play a central role by controlling cell differentiation at the transcriptional level. PRMT enzymatic activity is necessary for many cellular processes in hematological malignancies, such as the activation of cell cycle and proliferation, inhibition of apoptosis, DNA repair processes, RNA splicing, and transcription by methylating histone tails’ arginine. Chemical tools have been developed to inhibit the activity of PRMTs and have been tested in several models of hematological malignancies, including primary samples from patients, xenografts into immunodeficient mice, mouse models, and human cell lines. They show a significant effect by reducing cell viability and increasing the overall survival of mice. PRMT5 inhibitors have a strong therapeutic potential, as phase I clinical trials in hematological malignancies that use these molecules show promising results, thus, underlining PRMT inhibitors as useful therapeutic tools for cancer treatment in the future.

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PRMT6 activates cyclin D1 expression in conjunction with the transcription factor LEF1

Cited by 21 publications

References 58 publications

PRMT6-CDC20 facilitates glioblastoma progression via the degradation of CDKN1B

PRMT6-CDC20 facilitates glioblastoma progression via the degradation of CDKN1B

PRMT6-CDC20 facilitates glioblastoma progression via the degradation of CDKN1B

Protein Arginine Methyltransferases as Therapeutic Targets in Hematological Malignancies

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