Regulation of Cullin-RING E3 ligase dynamics by Inositol hexakisphosphate

Scott, Daniel C.; Kleiger, Gary

doi:10.1073/pnas.2001683117

Cited by 3 publications

(3 citation statements)

References 25 publications

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“…IP 6 is a multifunctional metabolite that serves as a structural cofactor in several protein and protein complexes (1). We recently identified a "glue"-like role for IP 6 in linking CRLs with their cognate deneddylase: the CSN, thereby regulating the neddylation status and catalytic cycle of CRLs (11,27,37,38). Consistent with suramin-mediated IP 6 depletion, cellular interactions between CSN and Cullin 4A (Cul4A) are significantly diminished by suramin (Fig.…”

Section: Suramin Regulates Crl-csn Complex Formation and Crl Activation In An Ip5k/ip 6 -Dependent Mannermentioning

confidence: 73%

Suramin and NF449 are IP5K inhibitors that disrupt inositol hexakisphosphate–mediated regulation of cullin–RING ligase and sensitize cancer cells to MLN4924/pevonedistat

Zhang

Shi

et al. 2020

Journal of Biological Chemistry

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Inositol hexakisphosphate (IP6) is an abundant metabolite synthesized from inositol 1,3,4,5,6-pentakisphosphate [Ins(1,3,4,5,6)P5, or IP5] by the single Ins(1,3,4,5,6)P5 2-kinase (IP5K/IPPK). Genetic and biochemical studies have shown that IP6 usually functions as a structural cofactor in protein(s) mediating mRNA export, DNA repair, necroptosis, 3D genome organization, HIV infection, and cullin RING ligase (CRL) deneddylation. However, it remains unknown whether pharmacological perturbation of cellular IP6 levels affects any of these processes. Here, we performed screening for small molecules that regulate human IP5K activity, revealing that the antiparasitic drug and polysulfonic compound suramin efficiently inhibits IP5K in vitro and in vivo. Results from docking experiments and biochemical validations suggested that suramin targets IP5K in a distinct bidentate manner by concurrently binding to the ATP- and IP5-binding pockets, thereby inhibiting both IP5 phosphorylation and IP5-independent ATP hydrolysis. NF449, a suramin analog with additional sulfonate moieties, more potently inhibited IP5K. Both suramin and NF449 disrupted IP6-dependent sequestration of CRL by the deneddylase COP9 Signalosome (CSN), thereby affecting CRL activity cycle and component dynamics in an IP5K-dependent manner. Finally, nontoxic doses of suramin, NF449, or NF110 exacerbates the loss of cell viability elicited by the neddylation inhibitor and clinical trial drug MLN4924/pevonedistat, suggesting synergistic effects. Suramin and its analogs provide structural templates for designing potent and specific IP5K inhibitors, which could be used in combination therapy along with MLN4924/pevonedistat. IP5K is a potential mechanistic target of suramin, accounting for suramin’s therapeutic effects.

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Section: Suramin Regulates Crl-csn Complex Formation and Crl Activation In An Ip5k/ip 6 -Dependent Mannermentioning

confidence: 73%

Suramin and NF449 are IP5K inhibitors that disrupt inositol hexakisphosphate–mediated regulation of cullin–RING ligase and sensitize cancer cells to MLN4924/pevonedistat

Zhang

Shi

et al. 2020

Journal of Biological Chemistry

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“…It seems that the inhibition of the phosphorylation-based activation of key molecular targets is a basic mechanism through which IP6 interferes with specific cellular and biological functions [ 67 ]. Very recently, the regulation of Cullin-RING E3 ligase dynamics by IP6 has been suggested [ 74 ]. Most of the current therapeutic molecular glues that target disease-causing proteins for degradation utilize the largest family of ubiquitin ligases in humans, the Cullin-RING (Really Interesting New Gene) ligases (CRLs).…”

Section: Anticancer Activity Of Ip6mentioning

confidence: 99%

“…Most of the current therapeutic molecular glues that target disease-causing proteins for degradation utilize the largest family of ubiquitin ligases in humans, the Cullin-RING (Really Interesting New Gene) ligases (CRLs). Because, IP6 causes G1 arrest by down-regulating p21 and p27, and since both p21 and p27 are well-defined substrates for CRL1- and CRL4-based ubiquitin ligases, it has been tempting to speculate that at least some degree of IP6’s anticancer activity might come from increased down-regulation of CRL function, thus stabilizing p21 and p27 to promote G1 arrest [ 74 ].…”

Section: Anticancer Activity Of Ip6mentioning

confidence: 99%

Inositol Hexaphosphate (IP6) and Colon Cancer: From Concepts and First Experiments to Clinical Application

Vučenik

Družijanić

2020

Molecules

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Multiple human health-beneficial effects have been related to highly phosphorylated inositol hexaphosphate (IP6). This naturally occurring carbohydrate and its parent compound, myo-inositol (Ins), are abundantly present in plants, particularly in certain high-fiber diets, but also in mammalian cells, where they regulate important cellular functions. However, the striking and broad-spectrum anticancer activity of IP6, consistently demonstrated in different experimental models, has been in a spotlight of the scientific community dealing with the nutrition and cancer during the last several decades. First experiments were performed in colon cancer 30 years ago. Since then, it has been shown that IP6 reduces cell proliferation, induces apoptosis and differentiation of malignant cells with reversion to normal phenotype, affecting several critical molecular targets. Enhanced immunity and antioxidant properties also contribute to the tumor cell destruction. Although Ins possesses a modest anticancer potential, the best anticancer results were obtained from the combination of IP6 + Ins. Here we review the first experimental steps in colon cancer, when concepts and hypotheses were put together almost without real knowledge and present clinical studies, that were initiated in colon cancer patients. Available as a dietary supplement, IP6 + Ins has been shown to enhance the anticancer effect of conventional chemotherapy, controls cancer metastases, and improves quality of life in cancer patients. Emerging clinical and still vast amount of experimental data suggest its role either as an adjuvant or as an “alternative” to current chemotherapy for cancer.

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Nuclear phosphoinositide signaling promotes YAP/TAZ-TEAD transcriptional activity in breast cancer

Jung,

Baek,

Wooldrik

et al. 2024

EMBO J

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The Hippo pathway effectors Yes-associated protein 1 (YAP) and its homolog TAZ are transcriptional coactivators that control gene expression by binding to TEA domain (TEAD) family transcription factors. The YAP/TAZ–TEAD complex is a key regulator of cancer-specific transcriptional programs, which promote tumor progression in diverse types of cancer, including breast cancer. Despite intensive efforts, the YAP/TAZ–TEAD complex in cancer has remained largely undruggable due to an incomplete mechanistic understanding. Here, we report that nuclear phosphoinositides function as cofactors that mediate the binding of YAP/TAZ to TEADs. The enzymatic products of phosphoinositide kinases PIPKIα and IPMK, including phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4,5-trisphosphate (P(I3,4,5)P3), bridge the binding of YAP/TAZ to TEAD. Inhibiting these kinases or the association of YAP/TAZ with PI(4,5)P2 and PI(3,4,5)P3 attenuates YAP/TAZ interaction with the TEADs, the expression of YAP/TAZ target genes, and breast cancer cell motility. Although we could not conclusively exclude the possibility that other enzymatic products of IPMK such as inositol phosphates play a role in the mechanism, our results point to a previously unrecognized role of nuclear phosphoinositide signaling in control of YAP/TAZ activity and implicate this pathway as a potential therapeutic target in YAP/TAZ-driven breast cancer.

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Regulation of Cullin-RING E3 ligase dynamics by Inositol hexakisphosphate

Cited by 3 publications

References 25 publications

Suramin and NF449 are IP5K inhibitors that disrupt inositol hexakisphosphate–mediated regulation of cullin–RING ligase and sensitize cancer cells to MLN4924/pevonedistat

Suramin and NF449 are IP5K inhibitors that disrupt inositol hexakisphosphate–mediated regulation of cullin–RING ligase and sensitize cancer cells to MLN4924/pevonedistat

Inositol Hexaphosphate (IP6) and Colon Cancer: From Concepts and First Experiments to Clinical Application

Nuclear phosphoinositide signaling promotes YAP/TAZ-TEAD transcriptional activity in breast cancer

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