EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis

Feng, Haizhong; López, Giselle Y.; Kim, Chung Kwon; Alvarez, Angel A.; Duncan, Chris; Nishikawa, Ryo; Nagane, Motoo; Su, An Jey A.; Auron, Philip E.; Hedberg, Matthew L.; Wang, Lin; Raizer, Jeffery J.; Kessler, John A.; Parsa, Andrew T.; Gao, Wei; Kim, Sung Hak; Minata, Mutsuko; Nakano, ﻿Ichiro; Grandis, Jennifer R.; McLendon, Roger E.; Bigner, Darell D.; Lin, Hui Kuan; Furnari, Frank B.; Cavenee, Webster K.; Hu, Bo; Yan, Hai; Cheng, Shi Yuan

doi:10.1172/jci73093

Cited by 80 publications

(92 citation statements)

References 49 publications

(114 reference statements)

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“…To further determine whether KAT6A is critical for glioma tumorigenesis, we employed an orthotopic GBM model as we previously described (26). U87 GBM cells transduced with shKAT6A-1, shKAT6A-2 or shControl were separately implanted intracranially to generate orthotopic xenografts in immunocompromised mice.…”

Section: Resultsmentioning

confidence: 99%

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Histone Acetyltransferase KAT6A Upregulates PI3K/AKT Signaling through TRIM24 Binding

Feng

Hou

et al. 2017

Cancer Research

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Lysine acetyltransferase KAT6A is a chromatin regulator that contributes to histone modification and cancer, but the basis of its actions are not well understood. Here we identify a KAT6A signaling pathway that facilitates glioblastoma (GBM) where it is upregulated. KAT6A expression was associated with GBM patient survival. KAT6A silencing suppressed cell proliferation, cell migration, colony formation and tumor development in an orthotopic mouse xenograft model system. Mechanistic investigations demonstrated that KAT6A acetylates lysine 23 of histone H3 (H3K23), which recruits the nuclear receptor binding protein TRIM24 to activate PIK3CA transcription, thereby enhancing PI3K/AKT signaling and tumorigenesis. Overexpressing activated AKT or PIK3CA rescued the growth inhibition due to KAT6A silencing. Conversely, the pan-PI3K inhibitor LY294002 abrogated the growth-promoting effect of KAT6A. Overexpression of KAT6A or TRIM24, but not KAT6A acetyltransferase activity- deficient mutants or TRIM24 mutants lacking H3K23ac binding sites promoted PIK3CA expression, AKT phosphorylation and cell proliferation. Taken together, our results define an essential role of KAT6A in glioma formation, rationalizing its candidacy as a therapeutic target for GBM treatment.

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Section: Resultsmentioning

confidence: 99%

“…Since AKT activation is important for histone acetyltransferase function (27-30) and glioma cell proliferation (26), we determined the effect of KAT6A knockdown on phosphorylation of AKT (p-AKT) in U87 and LN229 GBM cells. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Histone Acetyltransferase KAT6A Upregulates PI3K/AKT Signaling through TRIM24 Binding

Feng

Hou

et al. 2017

Cancer Research

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“…U87 neurosphere cells were seeded into 96-well round bottom plates and treated with vehicle (DMSO) alone or rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), or erlotinib, an epidermal growth factor receptor (EGFR) inhibitor that was previously shown to attenuate neurosphere size (12). To investigate whether the data obtained by our neurosphere assay correlate with cell viability, duplicate experiments were done in parallel for simultaneous analysis by the neurosphere assay and a water-soluble tetrazolium salt-1 (WST-1) proliferation assay as described previously (13).…”

Section: Methods Summarymentioning

confidence: 99%

A Simple, Low-Cost Staining Method for Rapid-Throughput Analysis of Tumor Spheroids

et al. 2016

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Tumor spheroids are becoming an important tool for the investigation of cancer stem cell (CSC) function in tumors; thus, low-cost and high-throughput methods for drug screening of tumor spheroids are needed. Using neurospheres as non-adherent three-dimensional (3-D) cultures, we developed a simple, low-cost acridine orange (AO)–based method that allows for rapid analysis of live neurospheres by fluorescence microscopy in a 96-well format. This assay measures the cross-section area of a spheroid, which corresponds to cell viability. Our novel method allows rapid screening of a panel of anti-proliferative drugs to assess inhibitory effects on the growth of cancer stem cells in 3-D cultures.

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“…It is conceivable that ESDN intracellular domain can similarly be involved in its interactions with IR and adaptor proteins, APS and Grb10. Previous work has implicated ESDN in regulation of VEGF, PDGF, and epidermal growth factor (EGF) signal transduction (9,13,28). Our new findings on ESDN regulation of insulin signaling suggest that ESDN might regulate the biological effects of other growth factors.…”

Section: Discussionmentioning

confidence: 57%

The neuropilin-like protein ESDN regulates insulin signaling and sensitivity

Jung

Nie

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Insulin effects on cell metabolism, growth, and survival are mediated by its binding to, and activation of, insulin receptor. With increasing prevalence of insulin resistance and diabetes there is considerable interest in identifying novel regulators of insulin signal transduction. The transmembrane protein endothelial and smooth muscle cell-derived neuropilinlike protein (ESDN) is a novel regulator of vascular remodeling and angiogenesis. Here, we investigate a potential role of ESDN in insulin signaling, demonstrating that Esdn gene deletion promotes insulininduced vascular smooth muscle cell proliferation and migration. This is associated with enhanced protein kinase B and mitogen-activated protein kinase activation as well as insulin receptor phosphorylation. Likewise, insulin signaling in the liver, muscle, and adipose tissue is enhanced in Esdn Ϫ/Ϫ mice, and these animals exhibit improved insulin sensitivity and glucose homeostasis in vivo. The effect of ESDN on insulin signaling is traced back to its interaction with insulin receptor, which alters the receptor interaction with regulatory adaptor protein-E3 ubiquitin ligase pairs, adaptor protein with pleckstrin homology and Src homology 2 domain-c-Cbl and growth factor receptor bound protein 10-neuronal precursor cell-expressed developmentally downregulated 4. In conclusion, our findings establish ESDN as an inhibitor of insulin receptor signal transduction through a novel regulatory mechanism. Loss of ESDN potentiates insulin's metabolic and mitotic effects and provides insights into a novel therapeutic avenue.

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EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis

Cited by 80 publications

References 49 publications

Histone Acetyltransferase KAT6A Upregulates PI3K/AKT Signaling through TRIM24 Binding

Histone Acetyltransferase KAT6A Upregulates PI3K/AKT Signaling through TRIM24 Binding

A Simple, Low-Cost Staining Method for Rapid-Throughput Analysis of Tumor Spheroids

The neuropilin-like protein ESDN regulates insulin signaling and sensitivity

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