Novel PRMT5-mediated arginine methylations of HSP90A are essential for maintenance of HSP90A function in NDRG2low ATL and various cancer cells

Ichikawa, Tomonaga; Shanab, Obeid; Nakahata, Shingo; Shimosaki, Shunsuke; Manachai, Nawin; Ono, Masaya; Iha, Hidekatsu; Shimoda, Kazuya; Morishita, Kazuhiro

doi:10.1016/j.bbamcr.2019.118615

Cited by 11 publications

(37 citation statements)

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“…Only recently, a novel function of PRMT5 has been discovered—the enzyme has been implicated in regulating Hsp90A function as its knockdown results in the degradation of Hsp90A client proteins and cell apoptosis. As Hsp90A is a known cancer-related chaperone, targeting PRMT5 may have additional anticancer benefit in lifting a protection exerted by Hsp90A over a number of oncoproteins [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

L-Arginine/Nitric Oxide Pathway Is Altered in Colorectal Cancer and Can Be Modulated by Novel Derivatives from Oxicam Class of Non-Steroidal Anti-Inflammatory Drugs

Krzystek−Korpacka

Szczęśniak-Sięga

Szczuka

et al. 2020

Cancers

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L-arginine/nitric oxide pathway metabolites are altered in colorectal cancer (CRC). We evaluated underlying changes in pathway enzymes in 55 paired tumor/tumor-adjacent samples and 20 normal mucosa using quantitative-PCR and assessed the impact of classic and novel oxicam analogues on enzyme expression and intracellular metabolite concentration (LC-MS/MS) in Caco-2, HCT116, and HT-29 cells. Compared to normal mucosa, ARG1, PRMT1, and PRMT5 were overexpressed in both tumor and tumor-adjacent tissue and DDAH2 solely in tumor-adjacent tissue. Tumor-adjacent tissue had higher expression of ARG1, DDAH1, and DDAH2 and lower NOS2 than patients-matched tumors. The ARG1 expression in tumors increased along with tumor grade and reflected lymph node involvement. Novel oxicam analogues with arylpiperazine moiety at the thiazine ring were more effective in downregulating DDAHs and PRMTs and upregulating ARG2 than piroxicam and meloxicam. An analogue distinguished by propylene linker between thiazine’s and piperazine’s nitrogen atoms and containing two fluorine substituents was the strongest inhibitor of DDAHs and PRMTs expression, while an analogue containing propylene linker but no fluorine substituents was the strongest inhibitor of ARG2 expression. Metabolic reprogramming in CRC includes overexpression of DDAHs and PRMTs in addition to ARG1 and NOS2 and is not restricted to tumor tissue but can be modulated by novel oxicam analogues.

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Section: Discussionmentioning

confidence: 99%

L-Arginine/Nitric Oxide Pathway Is Altered in Colorectal Cancer and Can Be Modulated by Novel Derivatives from Oxicam Class of Non-Steroidal Anti-Inflammatory Drugs

Krzystek−Korpacka

Szczęśniak-Sięga

Szczuka

et al. 2020

Cancers

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“…14 Similar to RACK1, we found that NDRG2, a scaffold protein, is able to bind PP2A, which results in PP2A dephosphorylation of a group of signaling proteins, such as PTEN, NIK, PRMT5 and HSP90 (Figure 1), which cannot directly bind to PP2A. 6,15,16 PTEN can be dephosphorylated by PP2A only through NDRG2-mediated binding to PTEN. 6 The enzymatic activity of PTEN as a phosphatase is regulated by its phosphorylation at the C-terminus (Ser380, Thr382, and Thr383, the STT cluster), and when PTEN is phosphorylated at the PTEN-STT cluster, it is uncoupled from the cell membrane and loses its enzyme activity.…”

Section: What Role Doe S Ndrgpl Ay In Normal Cell S?mentioning

confidence: 86%

“…In addition to PP2A inhibitors, PP2A is affected by RACK1 adaptor (scaffold) protein, which recruits PP2A and deactivates transcription factor called IRF3 via the inhibition of type I interferon signaling 14 . Similar to RACK1, we found that NDRG2, a scaffold protein, is able to bind PP2A, which results in PP2A dephosphorylation of a group of signaling proteins, such as PTEN, NIK, PRMT5 and HSP90 (Figure 1), which cannot directly bind to PP2A 6,15,16 . PTEN can be dephosphorylated by PP2A only through NDRG2‐mediated binding to PTEN 6 .…”

Section: What Role Does Ndrg2 Play In Normal Cells?mentioning

confidence: 95%

“…50 PRMT5 expression did not change in normal CD4 + T cells or samples obtained from patients with ATLL. 16 In NDRG2-expressing normal cells, PRMT5 was observed in the cytoplasm and nucleus, and histones H4 and H3, which are the specific substrates of PRMT5, were arginine methylated. 16 However, in NDRG2-deficient ATLL cells, PRMT5 was localized in the cytoplasm, and the arginine methylation of histones was lost, indicating that PRMT5 is involved in the development of ATLL.…”

Section: (B)mentioning

confidence: 99%

“…In addition to that of the PI3K/AKT signaling pathway, the kinase activity of NIK in the non‐canonical NF‐κB pathway is regulated by phosphorylation via the NDRG2/PP2A complex 15 . Moreover, the enzyme activity of arginine methyltransferase of PRMT5 and the activation status of HSP90 are regulated by the NDRG2/PP2A complex 16 …”

Section: What Role Does Ndrg2 Play In Normal Cells?mentioning

confidence: 99%

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Pathophysiological significance of N‐myc downstream‐regulated gene 2 in cancer development through protein phosphatase 2A phosphorylation regulation

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PP2A and cancer epigenetics: a therapeutic opportunity waiting to happen

Tinsley

Allen-Petersen

2022

NAR Cancer

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The epigenetic state of chromatin is altered by regulators which influence gene expression in response to environmental stimuli. While several post-translational modifications contribute to chromatin accessibility and transcriptional programs, our understanding of the role that specific phosphorylation sites play is limited. In cancer, kinases and phosphatases are commonly deregulated resulting in increased oncogenic signaling and loss of epigenetic regulation. Aberrant epigenetic states are known to promote cellular plasticity and the development of therapeutic resistance in many cancer types, highlighting the importance of these mechanisms to cancer cell phenotypes. Protein Phosphatase 2A (PP2A) is a heterotrimeric holoenzyme that targets a diverse array of cellular proteins. The composition of the PP2A complex influences its cellular targets and activity. For this reason, PP2A can be tumor suppressive or oncogenic depending on cellular context. Understanding the nuances of PP2A regulation and its effect on epigenetic alterations can lead to new therapeutic avenues that afford more specificity and contribute to the growth of personalized medicine in the oncology field. In this review, we summarize the known PP2A-regulated substrates and potential phosphorylation sites that contribute to cancer cell epigenetics and possible strategies to therapeutically leverage this phosphatase to suppress tumor growth.

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Novel PRMT5-mediated arginine methylations of HSP90A are essential for maintenance of HSP90A function in NDRG2low ATL and various cancer cells

Cited by 11 publications

References 50 publications

L-Arginine/Nitric Oxide Pathway Is Altered in Colorectal Cancer and Can Be Modulated by Novel Derivatives from Oxicam Class of Non-Steroidal Anti-Inflammatory Drugs

L-Arginine/Nitric Oxide Pathway Is Altered in Colorectal Cancer and Can Be Modulated by Novel Derivatives from Oxicam Class of Non-Steroidal Anti-Inflammatory Drugs

Pathophysiological significance of N‐myc downstream‐regulated gene 2 in cancer development through protein phosphatase 2A phosphorylation regulation

PP2A and cancer epigenetics: a therapeutic opportunity waiting to happen

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