Protein arginine methyltransferase 5 is essential for growth of lung cancer cells

Gu, Zhifeng; Gao, Shen; Zhang, Fahao; Wang, Zhiqiang; Ma, Wencai; Davis, R. Eric; Wang, Zhengxin

doi:10.1042/bj20120768

Cited by 127 publications

(128 citation statements)

References 43 publications

(59 reference statements)

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“…Ullman and colleagues reported that PRMT5 accelerates tumor growth by arginine methylation of tumor suppressor programmed cell death 4 (31). Gu et al (32) suggested that PRMT5 is essential for the growth of lung cancer cells. Wei et al (33) reported that PRMT5 is a potential oncoprotein that up-regulates G1 cyclins and cyclindependent kinases and the phosphoinositide 3-kinase/AKT signaling cascade.…”

Section: Discussionmentioning

confidence: 99%

PRMT5 dimethylates R30 of the p65 subunit to activate NF-κB

Wang

Miyagi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

209

221

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The ubiquitous inducible transcription factor NF-κB plays central roles in immune and inflammatory responses and in tumorigenesis. Complex posttranslational modifications of the p65 subunit (RelA) are a major aspect of the extremely flexible regulation of NF-κB activity. Although phosphorylation, acetylation, ubiquitination, and lysine methylation of NF-κB have been well described, arginine methylation has not yet been found. We now report that, in response to IL-1β, the p65 subunit of NF-κB is dimethylated on arginine 30 (R30) by protein-arginine methyltransferase 5 (PRMT5). Expression of the R30A and R30K mutants of p65 substantially decreased the ability of NF-κB to bind to κB elements and to drive gene expression. A model in which dimethyl R30 is placed into the crystal structure of p65 predicts new van der Waals contacts that stabilize intraprotein interactions and indirectly increase the affinity of p65 for DNA. PRMT5 was the only arginine methyltransferase that coprecipitated with p65, and its overexpression increased NF-κB activity, whereas PRMT5 knockdown had the opposite effect. Microarray analysis revealed that ∼85% of the NF-κB-inducible genes that are down-regulated by the R30A mutation are similarly down-regulated by knocking PRMT5 down. Many cytokine and chemokine genes are among these, and conditioned media from cells expressing the R30A mutant of p65 had much less NF-κB-inducing activity than media from cells expressing the wild-type protein. PRMT5 is overexpressed in many types of cancer, often to a striking degree, indicating that high levels of this enzyme may promote tumorigenesis, at least in part by facilitating NF-κB-induced gene expression.histone | mass spectrometry T he NF-κB family is comprised of two protein subfamilies: c-Rel, RelB, and RelA (p65), which include transactivation domains in their C termini, and p100 (p52) and p105 (p50), which include a number of ankyrin repeats in their C termini and have transrepressive functions. All family members include an N-terminal DNA-binding region, the Rel homology domain (1). In the absence of an activating stimulus, NF-κB is located in the cytoplasm in a complex with the inhibitory IκB protein. In the classic pathway of NF-κB activation, extracellular signals activate IκB kinase, which phosphorylates IκBα, leading to its ubiquitination and degradation by proteasomes. NF-κB, liberated from IκB, translocates to the nucleus to regulate its target genes (2). The NF-κB pathway is regulated by means of several different posttranslational modifications, including ubiquitination, phosphorylation, acetylation, sumoylation, and nitrosylation (3). The recent work of several laboratories has revealed the reversible methylation of nonhistone proteins by enzymes that were discovered on the basis of their activities toward histones. For NF-κB, we found that in response to an activating signal, such as treatment with IL-1β, the p65 subunit is reversibly methylated on two specific lysine residues by chromatin remodeling enzymes in ways that profoundly aff...

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Section: Discussionmentioning

confidence: 99%

PRMT5 dimethylates R30 of the p65 subunit to activate NF-κB

Wang

Miyagi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

209

221

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“…Although recurrent mutations of PRMT5 have not been observed in cancer cells, PRMT5 expression is upregulated in human leukemia, lymphoma, and in many solid tumors, including gastric, colorectal, and lung cancer tumors (15). PRMT5 promotes the proliferation of lung and ovarian cancer cells, rendering it an attractive therapeutic target in these diseases (16,17).…”

Section: Introductionmentioning

confidence: 99%

Arginine methyltransferase PRMT5 is essential for sustaining normal adult hematopoiesis

Liu¹,

Cheng

Hamard

et al. 2015

Journal of Clinical Investigation

131

152

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R e s e a R c h a R t i c l e3 5 3 3 jci.orgVolume 125 Number 9 September 2015 levels decreased dramatically, suggesting important posttranscriptional regulation of PRMT5 expression in these cells. Since straight Prmt5-KO mice die before birth (12), we generated Prmt5-conditional KO mice by first crossing Prmt5 FLIP-OUT mice (obtained from the European Mutant Mouse Archive [EMMA]) with Flp recombinase-expressing transgenic (Tg) mice to generate Prmt5-floxed mice, whereby exon 7 of the Prmt5 time PCR (qPCR) ( Figure 1A) and Western blot analysis ( Figure 1B). Prmt5 mRNA and protein levels were readily detected in HSPCs, with little change in mRNA levels in the various stem and progenitor cell populations. However, when cells underwent myeloid, erythroid, or lymphoid differentiation, PRMT5 protein levels decreased to 5% to 24% of the levels seen in HSPCs. Although Prmt5 mRNA was maintained in differentiated B cells, its protein BM cells and found a complete loss of this modification 7 days after Cre induction ( Figure 1C), suggesting that PRMT5 is indeed the major type 2 PRMT in these cells. Deletion of PRMT5 during adult hematopoiesis leads to severe cytopenias. The deletion of PRMT5 in 2-month-old mice had a profound effect on hematopoiesis. Two weeks after the first poly(I:C) injection, the Mx1Cre + Prmt5 fl/fl mice developed severe pallor due to anemia, and most of these PRMT5-deleted mice were moribund 1 to 2 days later, requiring euthanasia. Analysis of the peripheral blood of these mice revealed severe pancytopenia, with a more than 10-fold decrease in wbc, a 5-fold decrease in rbc, and a 100-fold decrease in platelet counts 15 days after Cre induction ( Figure 1D). BM cellularity of the PRMT5-deleted mice was reduced by more than 50% on day 7 and by more than 95% on day 15 ( Figure 1E), consistent with the development of aplastic anemia ( Figure 1G). While PRMT5 loss had little effect on spleen weight (or cellularity) on day 15 (Supplemental Figure 2, A and B), the size and cellularity of the thymus were significantly reduced on day 15 gene was flanked by 2 LoxP sites (Supplemental Figure 1A; mice and Mx1Cre-negative littermate controls. To delete Prmt5 in hematopoietic cells, 2 i.p. injections of poly(I:C) (10 mg/kg on days 0 and 1) were given to both the Mx1Cre -and Mx1Cre + Prmt5-floxed mice. Prmt5 loss was confirmed by PCR analysis of genomic DNA (Supplemental Figure 1B), by quantitative qPCR to detect Prmt5 mRNA (Supplemental Figure 1C), and by Western blot analysis to detect PRMT5 protein (Supplemental Figure 1D). This injection strategy was used in all subsequent experiments. Interestingly, loss of PRMT5 triggered the loss of MEP50 protein (Supplemental Figure 1D), a cofactor that is required for the enzymatic activity of PRMT5 on histones, without changing Mep50 mRNA levels (data not shown). This suggests a probable posttranscriptional effect of PRMT5 on MEP50 protein levels. We also determined the overall level of symmetrically dimethylated arginine in PRMT5-deleted and Prmt5 Δ/Δ mice (n = 3). P...

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“…1D). Since PRMT5 expression is also required for the growth of lung cancer cells (A549) [3], we transfected these reporter genes into A549 cells and observed that the reporter gene activity of B5 in A549 was 2-fold higher than that in LNCaP and PC-3 cells, though a comparable reporter gene activity of B6 and B7 was observed in all three cell lines (Fig. 1D).…”

Section: Resultsmentioning

confidence: 99%

“…It has been reported that PRMT5 may function as an oncogene to promote cancer cell growth [1–3, 5–7, 9, 10]. Although NF-Y directly regulates transcription of many target genes to control cell cycle progression, cell proliferation and cell survival [12, 13, 15, 17], our finding that NF-Y transcriptionally activates PRMT5 expression suggests that NF-Y may also regulate cancer cell growth by controlling the expression level of PRMT5, an emerging epigenetic enzyme that functions as an oncogene in human cancers [1].…”

Section: Discussionmentioning

confidence: 99%

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Transcriptional activation of PRMT5 by NF-Y is required for cell growth and negatively regulated by the PKC/c-Fos signaling in prostate cancer cells

Zhang

Zha

et al. 2014

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Protein arginine methyltransferase 5 (PRMT5) symmetrically methylates arginine residues of histones and non-histone protein substrates and regulates a variety of cellular processes through epigenetic control of target gene expression or post-translational modification of signaling molecules. Recent evidence suggests that PRMT5 may function as an oncogene and its overexpression contributes to the development and progression of several human cancers. However, the mechanism underlying the regulation of PRMT5 expression in cancer cells remains largely unknown. In the present study, we have mapped the proximal promoter of PRMT5 to the −240 bp region and identified nuclear transcription factor Y (NF-Y) as a critical transcription factor that binds to the two inverted CCAAT boxes and regulates PRMT5 expression in multiple cancer cell lines. Further, we present evidence that loss of PRMT5 is responsible for cell growth inhibition induced by knockdown of NF-YA, a subunit of NF-Y that forms a heterotrimeric complex with NF-YB and NF-YC for function. Significantly, we have found that activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) in LNCaP prostate cancer cells down-regulates the expression of NF-YA and PRMT5 at the transcription level in a c-Fos-dependent manner. Given that down-regulation of several PKC isozymes is implicated in the development and progression of several human cancers, our findings suggest that the PKC-c-Fos-NF-Y signaling pathway may be responsible for PRMT5 overexpression in a subset of human cancer patients.

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Protein arginine methyltransferase 5 is essential for growth of lung cancer cells

Cited by 127 publications

References 43 publications

PRMT5 dimethylates R30 of the p65 subunit to activate NF-κB

PRMT5 dimethylates R30 of the p65 subunit to activate NF-κB

Arginine methyltransferase PRMT5 is essential for sustaining normal adult hematopoiesis

Transcriptional activation of PRMT5 by NF-Y is required for cell growth and negatively regulated by the PKC/c-Fos signaling in prostate cancer cells

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