Spectomycin B1 as a Novel SUMOylation Inhibitor That Directly Binds to SUMO E2

Hirohama, Mikako; Kumar, Ashutosh; Fukuda, Isao; Matsuoka, Seiji; Igarashi, Yasuhiro; Saitoh, Hisato; Takagi, Motoki; Shin‐ya, Kazuo; Honda, Kaori; Kondoh, Yasumitsu; Saito, Tamio; Nakao, Yoichi; Osada, Hiroyuki; Zhang, Kam Y. J.; Yoshida, Minoru; Ito, Akihiro

doi:10.1021/cb400630z

Cited by 87 publications

(64 citation statements)

References 24 publications

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“…Ubc9 is frequently upregulated in various types of cancers and plays a critical role in cancer progression and metastasis [25e28]. Ubc9 thus represents a novel target for therapeutic treatment of cancers [27,29]. Previous studies and ours reveal that the N-terminal region of Ubc9 regulates not only the formation of Ubc9~SUMO thioester, an essential step for SUMOylation, but also Ubc9 nuclear localization for efficient SUMOylation by directly interacting with SAE1/2, SUMOs and Imp13 [13e16,21].…”

Section: Discussionmentioning

confidence: 99%

Characterization of amino acid residues within the N-terminal region of Ubc9 that play a role in Ubc9 nuclear localization

Sekhri

Tao

Kaplan

et al. 2015

Biochemical and Biophysical Research Communications

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Section: Discussionmentioning

confidence: 99%

Characterization of amino acid residues within the N-terminal region of Ubc9 that play a role in Ubc9 nuclear localization

Sekhri

Tao

Kaplan

et al. 2015

Biochemical and Biophysical Research Communications

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“…In all experiments, inhibition of cellular sumoylation processes produced results similar to those observed with deletion of CTAR3, which suggests that any of the other tested methods of inhibiting sumoylation would be potential mechanisms by which LMP1-induced sumoylation could be inhibited in vivo during EBV latency. Two novel sumoylation inhibitors, spectomycin B1 and davidiin, have recently been identified (94,95). Davidiin, an ellagitannin, functions in a similar manner as ginkgolic acid and anacardic acid and inhibits the formation of the SUMO-activating enzyme-SUMO-1 intermediate (95).…”

Section: Discussionmentioning

confidence: 99%

“…Davidiin, an ellagitannin, functions in a similar manner as ginkgolic acid and anacardic acid and inhibits the formation of the SUMO-activating enzyme-SUMO-1 intermediate (95). Spectomycin B1 binds to Ubc9 and inhibits the SUMO-Ubc9 intermediate (94). Because our studies targeted the same steps of the sumoylation process, we propose that treatment of EBV-positive cells with either davidiin or spectomycin B1 would abrogate the LMP1 sumoylation-dependent maintenance of EBV latency, promoting viral reactivation.…”

Section: Discussionmentioning

confidence: 99%

LMP1-Induced Sumoylation Influences the Maintenance of Epstein-Barr Virus Latency through KAP1

Bentz

Moss

Whitehurst

et al. 2015

J Virol

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As a herpesvirus, Epstein-Barr virus (EBV) establishes a latent infection that can periodically undergo reactivation, resulting in lytic replication and the production of new infectious virus. Latent membrane protein-1 (LMP1), the principal viral oncoprotein, is a latency-associated protein implicated in regulating viral reactivation and the maintenance of latency. We recently found that LMP1 hijacks the SUMO-conjugating enzyme Ubc9 via its C-terminal activating region-3 (CTAR3) and induces the sumoylation of cellular proteins. Because protein sumoylation can promote transcriptional repression, we hypothesized that LMP1-induced protein sumoylation induces the repression of EBV lytic promoters and helps maintain the viral genome in its latent state. We now show that with inhibition of LMP1-induced protein sumoylation, the latent state becomes less stable or leakier in EBVtransformed lymphoblastoid cell lines. The cells are also more sensitive to viral reactivation induced by irradiation, which results in the increased production and release of infectious virus, as well as increased susceptibility to ganciclovir treatment. We have identified a target of LMP1-mediated sumoylation that contributes to the maintenance of latency in this context: KRABassociated protein-1 (KAP1). LMP1 CTAR3-mediated sumoylation regulates the function of KAP1. KAP1 also binds to EBV OriLyt and immediate early promoters in a CTAR3-dependent manner, and inhibition of sumoylation processes abrogates the binding of KAP1 to these promoters. These data provide an additional line of evidence that supports our findings that CTAR3 is a distinct functioning regulatory region of LMP1 and confirm that LMP1-induced sumoylation may help stabilize the maintenance of EBV latency. IMPORTANCE Epstein-Barr virus (EBV) latent membrane protein-1 (LMP1) plays an important role in the maintenance of viral latency. Previously, we documented that LMP1 targets cellular proteins to be modified by a ubiquitin-like protein (SUMO).We have now identified a function for this LMP1-induced modification of cellular proteins in the maintenance of EBV latency. Because latently infected cells have to undergo viral reactivation in order to be vulnerable to antiviral drugs, these findings identify a new way to increase the rate of EBV reactivation, which increases cell susceptibility to antiviral therapies. E pstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that causes persistent infection, generally asymptomatic, in over 90% of the world's population. Initially, the virus lytically infects oropharyngeal epithelial cells, producing virions containing linear genomes. The virus also quickly infects B lymphocytes, in which latent infection is established and persists in the form of episomes and subsets of viral latency genes are expressed. Periodically, latent virus can be reactivated and infectious virus is released in saliva (1). The processes that regulate the switch between latent and lytic infection have been studied for many years. One viral gene impli...

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“…Reduced Ubc9 expression suppresses growth of KRAS mutant colorectal cancer cells 117 , and Spectinomycin B1, an inhibitor of Ubc9, inhibits proliferation of MCF-7 breast cancer cells 118 . Reduced expression of the SUMO-activating enzyme subunit 2 (SAE2) and Ubc9 impair cell proliferation in cancer cells as does reduced expression of SAE2 alone in U2OS osteosarcoma cells.…”

Section: 0 Role Of Sumoylation In Cancermentioning

confidence: 99%

Targeting nuclear thymidylate biosynthesis

Chon

Stover

Field

2017

Molecular Aspects of Medicine

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Thymidylate (dTMP) biosynthesis plays an essential and exclusive function in DNA synthesis and proper cell division, and therefore has been an attractive therapeutic target. Folate analogues, known as antifolates, and nucleotide analogs that inhibit the enzymatic action of the de novo thymidylate biosynthesis pathway and are commonly used in cancer treatment. In this review, we examine the mechanisms by which the antifolate 5-fluorouracil, as well as other dTMP synthesis inhibitors, function in cancer treatment in light of emerging evidence that dTMP synthesis occurs in the nucleus. Nuclear localization of the de novo dTMP synthesis pathway requires modification of the pathway enzymes by the small ubiquitin-like modifier (SUMO) protein. SUMOylation is required for nuclear localization of the de novo dTMP biosynthesis pathway, and disruption in the SUMO pathway inhibits cell proliferation in several cancer models. We summarize evidence that the nuclear localization of the dTMP biosynthesis pathway is a critical factor in the efficacy of antifolate-based therapies that target dTMP synthesis.

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Spectomycin B1 as a Novel SUMOylation Inhibitor That Directly Binds to SUMO E2

Cited by 87 publications

References 24 publications

Characterization of amino acid residues within the N-terminal region of Ubc9 that play a role in Ubc9 nuclear localization

Characterization of amino acid residues within the N-terminal region of Ubc9 that play a role in Ubc9 nuclear localization

LMP1-Induced Sumoylation Influences the Maintenance of Epstein-Barr Virus Latency through KAP1

Targeting nuclear thymidylate biosynthesis

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