Design, Synthesis, and Evaluation of Isaindigotone Derivatives To Downregulate <i>c-myc</i> Transcription via Disrupting the Interaction of NM23-H2 with G-Quadruplex

Shan, Chan; Yan, Jin-wu; Wang, Yuqing; Che, Tong; Huang, Zhou-Li; Chen, Ai-Chun; Yao, Pei-Fen; Tan, Jia‐Heng; Ding, Li; Ou, Tian‐Miao; Gu, Lian‐Quan

doi:10.1021/acs.jmedchem.6b01218

Cited by 43 publications

(34 citation statements)

References 30 publications

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“…36 Furthermore, silencing NME2 expression through siRNA, 27 and disrupting NME2 interaction with the NHEIII 1 /G4 complex using synthetic compounds, resulted in decreased CMYC expression. 37,38 Taken together, these results strongly suggest a direct role of NME2 in regulation of CMYC gene transcription.…”

Section: Roles Of Nme1 and Nme2 In Transcriptional Regulationmentioning

confidence: 66%

Nuclear functions of NME proteins

Puts

Leonard

Pamidimukkala

et al. 2018

Laboratory Investigation

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The NME family of proteins is composed of 10 isoforms, designated NME1-10, which are diverse in their enzymatic activities and patterns of subcellular localization. Each contains a conserved domain associated with a nucleoside diphosphate kinase (NDPK) function, although not all are catalytically active. Several of the NME isoforms (NME1, NME5, NME7, and NME8) also exhibit a 3′–5′ exonuclease activity, suggesting roles in DNA proofreading and repair. NME1 and NME2 have been shown to translocate to the nucleus, although they lack a canonical nuclear localization signal. Binding of NME1 and NME2 to DNA does not appear to be sequence-specific in a strict sense, but instead is directed to single-stranded regions and/or other non-B-form structures. NME1 and NME2 have been identified as potential canonical transcription factors that regulate gene transcription through their DNA-binding activities. Indeed, the NME1 and NME2 isoforms have been shown to regulate gene expression programs in a number of cellular settings, and this regulatory function has been proposed to underlie their well-recognized ability to suppress the metastatic phenotype of cancer cells. Moreover, NME1 and, more recently, NME3, have been implicated in repair of both single- and double-stranded breaks in DNA. This suggests that reduced expression of NME proteins could contribute to the genomic instability that drives cancer progression. Clearly, a better understanding of the nuclear functions of NME1 and possibly other NME isoforms could provide critical insights into mechanisms underlying malignant progression in cancer. Indeed, clinical data indicate that the subcellular localization of NME1 may be an important prognostic marker in some cancers. This review summarizes putative functions of nuclear NME proteins in DNA binding, transcription, and DNA damage repair, and highlights their possible roles in cancer progression.

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Section: Roles Of Nme1 and Nme2 In Transcriptional Regulationmentioning

confidence: 66%

Nuclear functions of NME proteins

Puts

Leonard

Pamidimukkala

et al. 2018

Laboratory Investigation

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“…Interestingly, we observed that the NME2-binding motif ( Fig. 4 a ) was within also within a hTERT promoter PG4-forming sequence, and because NME2 and promoter G4 interactions have been reported before ( 21 , 30 ), we asked whether the G4 structure played any role in hTERT repression by NME2. Oligonucleotide representing the PG4-forming sequence adopted mixed parallel/antiparallel G4 structures in solution ( Fig.…”

Section: Resultsmentioning

confidence: 87%

Epigenetic suppression of human telomerase (hTERT) is mediated by the metastasis suppressor NME2 in a G-quadruplex–dependent fashion

Saha

Singh

Hussain

et al. 2017

Journal of Biological Chemistry

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Transcriptional activation of the human telomerase reverse transcriptase (hTERT) gene, which remains repressed in adult somatic cells, is critical during tumorigenesis. Several transcription factors and the epigenetic state of the hTERT promoter are known to be important for tight control of hTERT in normal tissues, but the molecular mechanisms leading to hTERT reactivation in cancer are not well-understood. Surprisingly, here we found occupancy of the metastasis suppressor non-metastatic 2 (NME2) within the hTERT core promoter in HT1080 fibrosarcoma cells and HCT116 colon cancer cells and NME2-mediated transcriptional repression of hTERT in these cells. We also report that loss of NME2 results in up-regulated hTERT expression. Mechanistically, additional results indicated that the RE1-silencing transcription factor (REST)–lysine-specific histone demethylase 1 (LSD1) co-repressor complex associates with the hTERT promoter in an NME2-dependent way and that this assembly is required for maintaining repressive chromatin at the hTERT promoter. Interestingly, a G-quadruplex motif at the hTERT promoter was essential for occupancy of NME2 and the REST repressor complex on the hTERT promoter. In light of this mechanistic insight, we studied the effects of G-quadruplex–binding ligands on hTERT expression and observed that several of these ligands repressed hTERT expression. Together, our results support a mechanism of hTERT epigenetic control involving a G-quadruplex promoter motif, which potentially can be targeted by tailored small molecules.

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“…On the other hand, other isaindigotone derivatives developed by the same group were found to bind to both NM23-H2 and the G-quadruplex, and showed remarkable abilities in disrupting G-quadruplex–NM23-H2 interactions. They exhibited significant effects on c-myc -related processes in SiHa cells, including inhibiting transcription and translation, inhibiting cellular proliferation, inducing apoptosis, and regulating cell cycle [16].…”

Section: G-quadruplexes and Their Binding Proteinsmentioning

confidence: 99%

“…However, compared to developing inhibitors for a specific enzyme or protein, selective interaction with the G-quadruplex structures in particular genome regions is difficult to achieve. An alternative strategy for discovering novel G-quadruplex-related compounds is to interfere with the binding between G-quadruplex-forming sequences and the binding proteins [15,16,17]. Considering the fact that the shifts between various secondary structures in nucleic acids actually are regulated by several proteins binding to the nucleic acids [18,19,20,21], this alternative strategy seems attractive.…”

Section: Introductionmentioning

confidence: 99%

Developing Novel G-Quadruplex Ligands: From Interaction with Nucleic Acids to Interfering with Nucleic Acid–Protein Interaction

et al. 2019

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G-quadruplex is a special secondary structure of nucleic acids in guanine-rich sequences of genome. G-quadruplexes have been proved to be involved in the regulation of replication, DNA damage repair, and transcription and translation of oncogenes or other cancer-related genes. Therefore, targeting G-quadruplexes has become a novel promising anti-tumor strategy. Different kinds of small molecules targeting the G-quadruplexes have been designed, synthesized, and identified as potential anti-tumor agents, including molecules directly bind to the G-quadruplex and molecules interfering with the binding between the G-quadruplex structures and related binding proteins. This review will explore the feasibility of G-quadruplex ligands acting as anti-tumor drugs, from basis to application. Meanwhile, since helicase is the most well-defined G-quadruplex-related protein, the most extensive research on the relationship between helicase and G-quadruplexes, and its meaning in drug design, is emphasized.

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Design, Synthesis, and Evaluation of Isaindigotone Derivatives To Downregulate c-myc Transcription via Disrupting the Interaction of NM23-H2 with G-Quadruplex

Cited by 43 publications

References 30 publications

Nuclear functions of NME proteins

Nuclear functions of NME proteins

Epigenetic suppression of human telomerase (hTERT) is mediated by the metastasis suppressor NME2 in a G-quadruplex–dependent fashion

Developing Novel G-Quadruplex Ligands: From Interaction with Nucleic Acids to Interfering with Nucleic Acid–Protein Interaction

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