Tumor cell‐specific inhibition of <scp>MYC</scp> function using small molecule inhibitors of the <scp>HUWE</scp>1 ubiquitin ligase

Peter, Stefanie; Bultinck, Jennyfer; Myant, Kevin; Jaenicke, Laura A.; Walz, Susanne; Müller, Judith; Gmachl, Michael; Treu, Matthias; Boehmelt, Guido; Ade, Carsten P.; Schmitz, W.; Wiegering, Armin; Otto, Christoph; Popov, Nikita; Sansom, Owen J.; Kraut, Norbert; Eilers, Martin

doi:10.15252/emmm.201403927

Cited by 99 publications

(109 citation statements)

References 52 publications

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“…We do acknowledge, however, that there are conflicting data published (14,24), and further acknowledge the possibility that Mule may function differently if it is overexpressed. Thus, we are attempting to understand whether the role of Mule in an established adenoma or tumor would differ from its role in adenoma initiation, and whether Mule overexpression in colon cancer results because of its signaling feedback that may occur if mutations render it inactive, as is classically the case for p53 in cancer (25).…”

Section: Discussionmentioning

confidence: 89%

E3 ubiquitin ligase Mule targets β-catenin under conditions of hyperactive Wnt signaling

Dominguez-Brauer

Khatun

Elia

et al. 2017

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

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Wnt signaling, named after the secreted proteins that bind to cell surface receptors to activate the pathway, plays critical roles both in embryonic development and the maintenance of homeostasis in many adult tissues. Two particularly important cellular programs orchestrated by Wnt signaling are proliferation and stem cell selfrenewal. Constitutive activation of the Wnt pathway resulting from mutation or improper modulation of pathway components contributes to cancer development in various tissues. Colon cancers frequently bear inactivating mutations of the adenomatous polyposis coli (APC) gene, whose product is an important component of the destruction complex that regulates β-catenin levels. Stabilization and nuclear localization of β-catenin result in the expression of a panel of Wnt target genes. We previously showed that Mule/ Huwe1/Arf-BP1 (Mule) controls murine intestinal stem and progenitor cell proliferation by modulating the Wnt pathway via c-Myc. Here we extend our investigation of Mule's influence on oncogenesis by showing that Mule interacts directly with β-catenin and targets it for degradation under conditions of hyperactive Wnt signaling. Our findings suggest that Mule uses various mechanisms to finetune the Wnt pathway and provides multiple safeguards against tumorigenesis.β-catenin | Mule | Wnt signaling | stem cells | colorectal cancer A ctivation of the Wnt pathway, named after the secreted proteins that bind to cell surface receptors to activate the pathway, plays a critical role in stem cell self-renewal, and thus the homeostasis of normal mammalian tissues. However, constitutive activation of Wnt signaling has been implicated in a broad range of cancers, including melanoma, hepatocellular carcinoma, and cancers of the prostate, thyroid, ovary, and breast (1-3). Perhaps the best-studied malignancy arising from the loss of regulation of the Wnt signaling pathway is colorectal cancer, which develops through a multistage process driven by the progressive accumulation of genetic mutations (4). The key initial activating mutation occurs in components of the Wnt pathway, but most commonly in APC.Canonical Wnt signaling involves a relay of protein interactions that serve to transmit a signal from the extracellular space to the plasma membrane. This signal is amplified in the cytoplasm and then directed to the nucleus to culminate in the activation of the Wnt target gene program. In molecular terms, when the glycoprotein Wnt is secreted into the extracellular space, it binds to a cell's Frizzled receptors in conjunction with the low-density lipoprotein receptorrelated proteins 5 and 6 (LRP5/6). The engagement of these receptors recruits the scaffolding protein Dishevelled (Dvl), leading to LRP5/6 phosphorylation and consequent recruitment of the scaffolding protein, Axin2 and glycogen synthase kinase 3 beta (GSK-3β). This recruitment results in disruption of the "destruction complex" that contains APC and normally binds to the signal transduction protein β-catenin to trigger its degradation. On Wn...

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Section: Discussionmentioning

confidence: 89%

E3 ubiquitin ligase Mule targets β-catenin under conditions of hyperactive Wnt signaling

Dominguez-Brauer

Khatun

Elia

et al. 2017

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

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“…1). Mechanistically, evidence was provided that HUWE1 inhibitors shift the activating MYC/MAX complex to a repressive MIZ1/MYC/MAX complex to deactivate a MYC-dependent oncogenic network (69), offering a further strategy to target MYC-addicted PDACs.…”

Section: Targeting Myc Indirectlymentioning

confidence: 99%

Concepts to Target MYC in Pancreatic Cancer

Wirth

Mahboobi

Krämer

et al. 2016

Molecular Cancer Therapeutics

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Current data suggest that MYC is an important signaling hub and driver in pancreatic ductal adenocarcinoma (PDAC), a tumor entity with a strikingly poor prognosis. No targeted therapies with a meaningful clinical impact were successfully developed against PDAC so far. This points to the need to establish novel concepts targeting the relevant drivers of PDAC, like KRAS or MYC. Here, we discuss recent developments of direct or indirect MYC inhibitors and their potential mode of action in PDAC.

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“…On the one hand, numerous studies carried out in different cancer cell lines have shown that the transcriptional repression of Miz-1 by c-Myc is relevant in many different stages of the carcinogenesis process (13). Interestingly, on the other hand, another recent study showed that high levels of Miz-1 cause the repression of c-Myc transcriptional transactivation (14). These results have led to the interesting hypothesis that the c-Myc/Miz-1 balance can dictate cell fate by controlling the transcription of gene networks (15).…”

Section: Ink4mentioning

confidence: 99%

“…In fact, in cancer cells, Miz-1 is found to co-localize with c-Myc at many transcription start sites where INR sequences are present. Most interestingly, Miz-1 can inhibit c-Myc transactivation of genes involved in tumorigenic programs (14,22). Despite such a critical role in the normal and oncogenic biology of the cell, it is not known whether all of the ZFs or only subsets bind and recognize the Miz-1 consensus sequence, the INR element, or other nonspecific DNA sequences.…”

Section: Ink4mentioning

confidence: 99%

Structural Insights into c-Myc-interacting Zinc Finger Protein-1 (Miz-1) Delineate Domains Required for DNA Scanning and Sequence-specific Binding

Bédard¹,

Roy²,

Montagne³

et al. 2017

Journal of Biological Chemistry

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Edited by Norma Allewellc-Myc-interacting zinc finger protein-1 (Miz-1) is a polyCys2His2 zinc finger (ZF) transcriptional regulator of many cell cycle genes. A Miz-1 DNA sequence consensus has recently been identified and has also unveiled Miz-1 functions in other cellular processes, underscoring its importance in the cell. Miz-1 contains 13 ZFs, but it is unknown why Miz-1 has so many ZFs and whether they recognize and bind DNA sequences in a typical fashion. Here, we used NMR to deduce the role of Miz-1 ZFs 1-4 in detecting the Miz-1 consensus sequence and preventing nonspecific DNA binding. In the construct containing the first 4 ZFs, we observed that ZFs 3 and 4 form an unusual compact and stable structure that restricts their motions. Disruption of this compact structure by an electrostatically mismatched A86K mutation profoundly affected the DNA binding properties of the WT construct. On the one hand, Miz1-4 WT was found to bind the Miz-1 DNA consensus sequence weakly and through ZFs 1-3 only. On the other hand, the four ZFs in the structurally destabilized Miz1-4 A86K mutant bound to the DNA consensus with a 30-fold increase in affinity (100 nM). The formation of such a thermodynamically stable but nonspecific complex is expected to slow down the rate of DNA scanning by Miz-1 during the search for its consensus sequence. Interestingly, we found that the motif stabilizing the compact structure between ZFs 3 and 4 is conserved and enriched in other long poly-ZF proteins. As discussed in detail, our findings support a general role of compact inter-ZF structures in minimizing the formation of off-target DNA complexes.Miz-1 (c-Myc-interacting zinc finger protein-1) is an 88-kDa protein that contains a BTB (Broad complex, Tramtrack, and Bric-a-brac)-POZ (poxvirus and zinc finger) (POZ) 3 domain at its N terminus followed by 13 ZFs. It was first identified as a direct interactor of the oncogenic protein c-Myc by yeast twohybrid screening (1). Miz-1 is an activator of cell cycle regulator genes, such as the cyclin-dependent kinase inhibitors p15CIP1 (p21), and p57 KIP2 (p57) (2-5). Miz-1 activates the transcription of those genes by recruiting different co-activators, such as the histone acetyltransferase p300 and the nucleophosmin (3, 6). Moreover, it was shown that in response to TGF-␤, Miz-1 forms a complex with the Smad 2/3/4 proteins to activate the expression of p15. This interaction was shown to involve a region located within the first four ZFs of Miz-1 and the MH1 domain of Smad 3 (7). Whereas the role of Miz-1 in cell cycle regulation is well established, recent studies have underlined its implication in other cell cycle-independent processes, such as autophagy, endocytosis, vesicular trafficking, inflammation and DNA repair (8 -11). Moreover, some cytoplasmic functions of Miz-1, such as its implication in the regulation of the Wnt pathway, are emerging, revealing the multifunctional nature of this transcription factor (12).c-Myc can directly bind Miz-1 and repress the expression of p15, p21, and p57, ...

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Tumor cell‐specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase

Cited by 99 publications

References 52 publications

E3 ubiquitin ligase Mule targets β-catenin under conditions of hyperactive Wnt signaling

E3 ubiquitin ligase Mule targets β-catenin under conditions of hyperactive Wnt signaling

Concepts to Target MYC in Pancreatic Cancer

Structural Insights into c-Myc-interacting Zinc Finger Protein-1 (Miz-1) Delineate Domains Required for DNA Scanning and Sequence-specific Binding

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