Metastases suppressor NM23-H2 interaction with G-quadruplex DNA within c-MYC promoter nuclease hypersensitive element induces c-MYC expression

Thakur, Ram Krishna; Kumar, Praveen; Halder, Kangkan; Verma, Anjali; Kar, Anirban; Parent, Jean‐Luc; Basundra, Richa; Kumar, Anuj; Chowdhury, Shantanu

doi:10.1093/nar/gkn919

Cited by 162 publications

(187 citation statements)

References 64 publications

(81 reference statements)

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“…NME2 regulates MYC transcription by binding to the nuclease hypersensitive element III (NHE III) region of the MYC promoter close to the transcription start site (35)(36)(37). Given the mode of action of stauprimide, we hypothesized that cancer cells with different genomic regulatory sequences around the NHE III region may respond differently to stauprimide.…”

Section: Resultsmentioning

confidence: 99%

Small molecule selectively suppresses MYC transcription in cancer cells

Bouvard

Lim

Ludka

et al. 2017

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

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Stauprimide is a staurosporine analog that promotes embryonic stem cell (ESC) differentiation by inhibiting nuclear localization of the MYC transcription factor NME2, which in turn results in downregulation of MYC transcription. Given the critical role the oncogene MYC plays in tumor initiation and maintenance, we explored the potential of stauprimide as an anticancer agent. Here we report that stauprimide suppresses MYC transcription in cancer cell lines derived from distinct tissues. Using renal cancer cells, we confirmed that stauprimide inhibits NME2 nuclear localization. Gene expression analysis also confirmed the selective down-regulation of MYC target genes by stauprimide. Consistent with this activity, administration of stauprimide inhibited tumor growth in rodent xenograft models. Our study provides a unique strategy for selectively targeting MYC transcription by pharmacological means as a potential treatment for MYCdependent tumors.MYC | stauprimide | NME2 | nuclear localization | cancer T he transcription factor MYC participates in diverse cellular processes by regulating the transcription of a large number of genes involved in gene expression, cell division, apoptosis, cell adhesion, stem cell self-renewal and differentiation, and metabolism (1-3). MYC is an oncogene whose expression is elevated in up to 75% of all cancers with various tissue origins (4); MYC expression levels also correlate with prognostic outcomes in patients of various types of malignancies (5, 6). In addition to its well-established roles in tumor initiation and cancer cell survival and proliferation, MYC has been shown to be involved in tumor microenvironment remodeling, drug resistance, and cancer stem cell maintenance (7-9). Recent studies have also revealed a role for MYC in regulating the transcription of immune checkpoint genes, including CD47 and PD-L1 in cancer cells, suggesting that MYC is involved in cancer escape from immune surveillance (10).Overexpression of MYC is able to induce malignant transformation in skin (11), lung (12), liver (13), breast (14, 15), and hematopoietic cells (16) in transgenic mouse models, and termination of MYC overexpression results in halted cancer cell proliferation, increased apoptosis and terminal differentiation, and tumor regression. Furthermore, inhibition of endogenous MYC by the inducible expression of a dominant-negative variant of MYC, Omomyc, is able to induce tumor regression in transgenic mouse models of lung cancer (17). More intriguingly, transient deactivation of MYC overexpression (18) and episodic expression of Omomyc (19) have been shown to induce irreversible tumor regression in osteosarcoma and lung cancer transgenic mouse models, suggesting the potential of MYCtargeted anticancer therapies.Drug discovery efforts have attempted to directly and indirectly modulate MYC-dependent transcription. For example, compounds have been identified that disrupt the interaction between MYC and its transcriptional partner MAX to suppress downstream gene transcription (20)(21)(22)(23)(2...

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Section: Resultsmentioning

confidence: 99%

Small molecule selectively suppresses MYC transcription in cancer cells

Bouvard

Lim

Ludka

et al. 2017

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

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“…These higher order structures are four-stranded intramolecular foldings of single-stranded DNA, formed by the stacking of two or more tetrads, each comprising four guanines connected by Hoogsteen hydrogen bonds and stabilized with monovalent cations. G4s are globular in nature, analogous to the tertiary structure of a protein, and they serve as the silencer element for MYC transcription, putatively through sequestration of transcriptional factor binding sites (33)(34)(35).In the present study we identified the ellipticine derivative GQC-05 (NSC338258) as a potent and selective stabilizer of the MYC G4 structure. We demonstrate that the activity of this compound is dependent on the presence and regulation of a G4 within the MYC promoter region and that it specifically modulates protein binding to the NHE III 1 .…”

mentioning

confidence: 75%

Demonstration that Drug-targeted Down-regulation of MYC in Non-Hodgkins Lymphoma Is Directly Mediated through the Promoter G-quadruplex

Brown

Danford

Gokhale

et al. 2011

Journal of Biological Chemistry

154

221

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Most transcription of the MYC proto-oncogene initiates in the near upstream promoter, within which lies the nuclease hypersensitive element (NHE) III 1 region containing the CT-element. This dynamic stretch of DNA can form at least three different topologies: single-stranded DNA, double-stranded DNA, or higher order secondary structures that silence transcription. In the current report, we identify the ellipticine analog GQC-05 (NSC338258) as a high affinity, potent, and selective stabilizer of the MYC G-quadruplex (G4). In cells, GQC-05 induced cytotoxicity with corresponding decreased MYC mRNA and altered protein binding to the NHE III 1 region, in agreement with a G4 stabilizing compound. We further describe a unique feature of the Burkitt's lymphoma cell line CA46 that allowed us to clearly demonstrate the mechanism and location of action of GQC-05 within this region of DNA and through the G4. Most importantly, these data present, as far as we are aware, the most direct evidence of intracellular G4-mediated control of a particular promoter.The MYC proto-oncogene is a key component of normal cell growth and differentiation, with roles in a multitude of cellular processes. Normally, this gene is subject to tight transcriptional regulation; however, aberrant MYC expression is a common feature in an estimated 80% of all human malignancies (1-3); it is estimated that one-seventh of cancer deaths in the United States are associated with alterations in the MYC gene or its expression (4). Deregulation can arise through a variety of mechanisms (5-13), but most often MYC is activated through alterations in cell signaling that lead to increased transcription (14).Deregulated MYC can lead to transformation (15), often as an early step in the process of multistage cancer development, and one on which all other mutations are based (16,17). Cancer cells appear to be addicted to a deregulated MYC (18), which can be the "Achilles heel", offering the potential for a therapeutic window (19,20). The ability to selectively and potently down-regulate MYC would have considerable potential for both efficacy and safety in a variety of tumor types.There are several upstream elements within the MYC promoter that can potentially undergo strand separation to form either single-stranded or other non-B-DNA structures (21), which play a critical role in transcriptional control of MYC: the distant Far Upstream Element acts as a cruise control element, Z-DNA found both in the far upstream and the promoter regions, and a GC-rich region within the proximal promoter that acts as an on/off switch (22-28). This near upstream core promoter region, which is responsible for the initiation of 80 -90% of MYC transcription (29), contains the GC-rich nuclease hypersensitive element (NHE) 2 III 1 to which doublestranded (Sp1) and single-stranded (CNBP and hnRNP k) transcriptional factors bind. Within the MYC gene's NHE III 1 , a 31-base pair element consisting of five repeats of the sequence (C/T)C(C/T)TCCCCA serves as the "on/off switch" for MYC trans...

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“…Nm23-H2 also binds to c-myc and NHE have a G4 motif that withhold c-myc expression and Nm23-H2 act as an activator of c-myc expression and there is decrease levels of Nm23-H2 leads to lower c-myc levels (Simonsson et al, 2000;Siddiqui-Jain et al, 2002). The decreased expression of Nm23-H2 are associated with metastatic potential and reduction in Nm23-H2 level in cancer cells reduced in c-myc expression that decreases apoptosis of the cancer cells enhancing metastasis (Zajac-Kaye, 2001;Thakur et al, 2009). Nm23-H5 involves in nucleotide metabolism of the germ cells which are expressed in testis close similar to Nm23-H1, H2, H3 and H4 depending upon the type of the tissue.…”

Section: Differential Expression Of Nm23 Gene Family and Regulationmentioning

confidence: 99%

Targeting Tumor Metastasis by Regulating Nm23 Gene Expression

Prabhu

Siddikuzzaman²,

Grace³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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The Nm23 gene is a metastatic suppressor identified in a melanoma cell line and expressed in different tumors where their levels of expression are associated with reduced or increased metastatic potential. Nm23 is one of the over 20 metastasis suppressor genes (MSGs) confirmed in vivo. It is highly conserved from yeast to human, implying a critical developmental function. Tumors with alteration of the p53 gene and reduced expression of the Nm23 gene are more prone to metastasis. Nm23-H1 has 3'-5' exonuclease activity. This review focuses on the role of Nm23 in cancer progression and also a potential novel target for cancer therapy.

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Metastases suppressor NM23-H2 interaction with G-quadruplex DNA within c-MYC promoter nuclease hypersensitive element induces c-MYC expression

Cited by 162 publications

References 64 publications

Small molecule selectively suppresses MYC transcription in cancer cells

Small molecule selectively suppresses MYC transcription in cancer cells

Demonstration that Drug-targeted Down-regulation of MYC in Non-Hodgkins Lymphoma Is Directly Mediated through the Promoter G-quadruplex

Targeting Tumor Metastasis by Regulating Nm23 Gene Expression

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