Sulforaphane suppresses PRMT5/MEP50 function in epidermal squamous cell carcinoma leading to reduced tumor formation

Saha, Kamalika; Fisher, Mike; Adhikary, Gautam; Grun, Daniel; Eckert, Richard L.

doi:10.1093/carcin/bgx044

Cited by 22 publications

(26 citation statements)

References 65 publications

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“…Proliferation of OPCs in vivo was not affected by loss of Prmt5 (Fig. 3d ) and this was in contrast with previous reports on the effect of PRMT5 inhibition in cancer cells 40 , 41 . To further ascertain that PRMT5 did not affect proliferation, we treated primary cultures of OPCs with GSK591, a selective inhibitor of PRMT5 (which inhibits symmetric dimethylation of arginine containing substrates by the PRMT5/MEP50 complex 42 ) (Fig.…”

Section: Resultscontrasting

confidence: 99%

PRMT5-mediated regulation of developmental myelination

et al. 2018

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Oligodendrocytes (OLs) are the myelin-forming cells of the central nervous system. They are derived from differentiation of oligodendrocyte progenitors through a process requiring cell cycle exit and histone modifications. Here we identify the histone arginine methyl-transferase PRMT5, a molecule catalyzing symmetric methylation of histone H4R3, as critical for developmental myelination. PRMT5 pharmacological inhibition, CRISPR/cas9 targeting, or genetic ablation decrease p53-dependent survival and impair differentiation without affecting proliferation. Conditional ablation of Prmt5 in progenitors results in hypomyelination, reduced survival and differentiation. Decreased histone H4R3 symmetric methylation is followed by increased nuclear acetylation of H4K5, and is rescued by pharmacological inhibition of histone acetyltransferases. Data obtained using purified histones further validate the results obtained in mice and in cultured oligodendrocyte progenitors. Together, these results identify PRMT5 as critical for oligodendrocyte differentiation and developmental myelination by modulating the cross-talk between histone arginine methylation and lysine acetylation.

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Section: Resultscontrasting

confidence: 99%

PRMT5-mediated regulation of developmental myelination

et al. 2018

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“…We further detected the expression of NF-κBp65 protein in tumor tissues of nude mice, finding that injecting si-PRMT5+Si-LXRα for co-transfection could reverse the expression of LXRα protein and NF-κBp65 protein in tumor tissues of nude mice injected with si-PRMT5. A previous study also suggested that inhibition of PRMT5 could suppress the growth of tumors in vivo, 31 which further confirmed our conjecture.…”

Section: Discussionsupporting

confidence: 90%

<p>PRMT5 Promotes Aerobic Glycolysis and Invasion of Breast Cancer Cells by Regulating the LXRα/NF-κBp65 Pathway</p>

Han¹,

Wei²,

Wu³

2020

OTT

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Objective: To explore the effects of protein arginine methyltransferase 5 (PRMT5) on the biological function of breast cancer cells (BCCs) by regulating the liver X receptor α (LXRα)/NF-κBp65 pathway. Methods: A total of 80 patients with breast cancer (BC) admitted to our hospital were collected, and 80 breast cancer tissue specimens and 80 corresponding tumor-adjacent tissue specimens were sampled from them for analysis. The reverse transcription-polymerase chain reaction (RT-PCR) was employed to determine the expression of PRMT5 mRNA in the sampled tissues, and the Western blot to determine the expression of LXRα and NF-κBp65 proteins in the tissues and cells. The patients were followed up to analyze their 3-year survival rate. Stable and transient overexpression vectors and inhibition vectors were constructed and transfected into BCCs. The cell counting kit-8 (CCK8), transwell, and flow cytometry were adopted to analyze the proliferation, invasion, and apoptosis of transfected cells, on which the effects of PRMT5 on LXRα and NF-κBp65 proteins were analyzed. Results: PRMT5 was highly expressed in BC patients, and LXRα was lowly expressed in them, which had a high diagnostic value. Patients with high expression of PRMT5 showed a poor prognosis, and the expression of PRMT5 was related to the tumor size, pathological stage, differentiation, and metastatic in BC patients. Overexpressed PRMT5 enhanced the cell proliferation, invasion, and glycolysis abilities, weakened apoptosis ability, further lowered expression of LXRα and increased expression of NF-κBp65, while inhibited PRMT5 caused opposite results in those aspects. Up-regulating the expression of LXRα suppressed the proliferation, invasion, and aerobic glycolysis of BCCs and promoted their apoptosis, while inhibiting it posed opposite effects. The rescue experiment revealed that down-regulating the expression of PRMT5 could counteract the promotion of downregulation of LXRα on proliferation, invasion and glycolysis of BCCs, and the nude mouse tumorigenesis test revealed that PRMT5 induced tumor on nude mice by mediating LXRα/NF-κBp65. Conclusion: Inhibition of the PRMT5 expression can accelerate apoptosis of BCCs and weaken their proliferation, invasion, and aerobic glycolysis through the LXRα/NF-κBp65 pathway.

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“…To our knowledge, this is the first study to report such a correlation and our results further highlight the importance of PRMT5 as a potential HCC biomarker. In addition to in vivo studies, several in vitro experiments have revealed that depletion of PRMT5 induced a decrease in cancer cell survival (36) and proliferation (19,28,34,(36)(37)(38). While these phenotypes have been observed in various cancer cell lines, the exact molecular mechanisms remain to be established.…”

Section: Discussionmentioning

confidence: 99%

“…These results were in accordance with the previous finding that the depletion of PRMT5 modulated the expression of E-cadherin through interactions with Ajuba, to regulate the transcription factor Snail (6). However, earlier invasion analyses were performed under conditions whereby the PRMT5 siRNAs used induced a decrease in cell proliferation and/or survival (17,18,38). Decreased proliferation and survival can affect the invasion of cancer cells, thus reducing cell activity.…”

Section: Discussionmentioning

confidence: 99%

Protein arginine methyltransferase 5 is implicated in the aggressiveness of human hepatocellular carcinoma and controls the invasive activity of cancer cells

et al. 2018

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Protein arginine methyltransferase 5 (PRMT5) is a protein that catalyzes transfer of methyl groups to the arginine residues of proteins and is involved in diverse cellular and biological responses. While the participation of PRMT5 in cancer progression has been increasingly documented, its association with the invasive phenotype currently remains poorly understood. In the present study, we revealed that PRMT5 is overexpressed in human hepatocellular carcinoma (HCC) and in colon cancer and its depletion leads to the suppression of cell invasive activity via the reduction of the expression of MMP-2. Real-time quantitative RT-PCR analysis of 120 HCC patient tissues revealed the overexpression of PRMT5 in HCC and the association of PRMT5 with aggressive clinicopathological parameters, such as poorer differentiation (P=0.004), more frequent hepatic vein invasion (P=0.019), larger tumor size (P=0.011) and higher α-fetoprotein levels (P=0.020). Similarly to the data obtained with HCC, overexpression of PRMT5 was also displayed in colon cancer tissues, compared to matched non-tumor regions. Consistent with the significant association of the overexpression of PRMT5 with hepatic vein invasion in patient specimens, PRMT5 depletion via siRNA transfection led to a marked reduction in the invasion rate in both HCC and colon cancer cells. Reduced invasion associated with PRMT5 depletion was accompanied by a decrease in the expression of MMP-2. Collectively, our results indicated that PRMT5 overexpression in HCC and colon cancer cells contributed to their acquisition of aggressive characteristics, such as invasiveness, thus presenting a promising therapeutic target for the treatment of these diseases.

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Sulforaphane suppresses PRMT5/MEP50 function in epidermal squamous cell carcinoma leading to reduced tumor formation

Cited by 22 publications

References 65 publications

PRMT5-mediated regulation of developmental myelination

PRMT5-mediated regulation of developmental myelination

<p>PRMT5 Promotes Aerobic Glycolysis and Invasion of Breast Cancer Cells by Regulating the LXRα/NF-κBp65 Pathway</p>

Protein arginine methyltransferase 5 is implicated in the aggressiveness of human hepatocellular carcinoma and controls the invasive activity of cancer cells

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