Small molecule promotes β-catenin citrullination and inhibits Wnt signaling in cancer

Qu, Yi; Olsen, Jan Roger; Xing, Yuan; Cheng, Phil F.; Levesque, Mitchell P.; Brokstad, Karl Albert; Hoffman, Paul S.; Øyan, Anne Margrete; Zhang, Weidong; Kalland, Karl‐Henning; Ke, Xisong

doi:10.1038/nchembio.2510

Cited by 116 publications

(116 citation statements)

References 48 publications

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“…PADI2 catalyzes citrullination, whereby peptidylarginine is converted into peptidyl‐citrulline. Substrates of PADI2 include histones, vimentin, β‐ and γ‐actins, myelin basic protein, 26 and β‐catenin 27 . In preclinical models of breast cancer, 28‐32 prostate cancer, 21,33 gastric cancer, 20 and glioblastoma, 34 PADI2 inhibition or depletion decreased growth, migration, and extracellular vesicle release, and was synergistic with docetaxel and bortezomib in inducing apoptosis in tamoxifen‐resistant breast cancer 22 and bone marrow mesenchymal stem cells, 35 respectively.…”

Section: Discussionmentioning

confidence: 99%

Proteomic profiling of FBXW7‐mutant serous endometrial cancer cells reveals upregulation of PADI2, a potential therapeutic target

Urick

Bell

2020

Cancer Medicine

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Background:Despite advancements over the past decade revealing molecular aberrations characteristic of endometrial cancer (EC) subtypes, serous ECs remain difficult to treat and associated with poor outcomes. This is due, in part, to the rarity of these tumors within clinical trials and the inability to directly target the most frequent genomic abnormalities. One of the most commonly somatically mutated genes in serous ECs is the tumor suppressor F-box and WD repeat domain containing 7 (FBXW7). Methods: To identify changes in protein expression associated with FBXW7 mutation, we clustered regularly interspaced short palindromic repeats (CRISPR)-edited ARK4 FBXW7 nonmutant serous EC cells to insert recurrent FBXW7 mutations. We then compared the liquid chromatography tandem mass spectrometry-based proteomic profiles of CRISPR-edited ARK1 and ARK4 serous EC cells to matched parental cells. Results: Among distinct total and phosphorylated proteins that were significantly differentially expressed in FBXW7-mutant cell lines compared to matched parental lines, we identified increased PADI2 (peptidyl arginine deiminase 2) expression in all ARK1 and ARK4 CRISPR-edited FBXW7-mutant cell lines. We further confirmed the correlation between FBXW7 mutation and increased PADI2 expression in a third biological background, JHUEM-1 endometrioid EC cells. Finally, we established that PADI2 protein is expressed in primary serous endometrial tumors. Conclusion: Our findings provide novel insight into proteomic changes associated with FBXW7 mutation in serous ECs and identify PADI2 as a novel potential therapeutic target for these tumors.

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Section: Discussionmentioning

confidence: 99%

Proteomic profiling of FBXW7‐mutant serous endometrial cancer cells reveals upregulation of PADI2, a potential therapeutic target

Urick

Bell

2020

Cancer Medicine

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“…Wnt/b-catenin signaling is important for carcinogenesis of certain tumors, and PAD2-mediated citrullination was recently linked to this pathway (50). Antiparasitic drug temozolomide (NTZ) inhibited Wnt/b-catenin signaling through directly targeting PAD2 as demonstrated by co-immunoprecipitation studies.…”

Section: Citrullination Affecting Cancer Cell Signalingmentioning

confidence: 99%

Citrullination in Cancer

2019

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Posttranslational modifications of proteins have been implicated in pathogenesis of numerous diseases. Arginine deimination (also known as citrullination) has a principal role in progression of rheumatoid arthritis through generation of autoantibodies and exacerbation of the inflammatory response. Recently, multiple research groups provided solid evidence of citrullination being in control of cancer progression; however, there is no comprehensive overview of these findings. This article summarizes and critically reviews the influence of citrul-lination on different aspects of tumor biology, including (i) regulation of apoptosis and differentiation, (ii) promoting EMT and metastasis, and (iii) potential use of citrullinated antigens for immunotherapy. In addition, (iv) the role of citrullination as a cancer biomarker and (v) implication of neutrophil extracellular traps in tumorigenesis are discussed. In summary, current findings testify to the significance of arginine deimination in tumor biology and thus more basic and translational studies are needed to further explore this topic. Brief Overview of PAD Biology and Function in Physiologic ConditionsPADs are a group of five Ca 2þ -dependent enzymes (PAD1-4 and PAD6), sharing 70% to 95% sequence homology and expressed in a wide range of tissues and organs ( Fig. 1D;

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“…The nonradioactive metabolic labeling assay mainly includes four parts: nascent protein labeling, immunoprecipitation of the protein of interest (for example, TCF4), Click-iT reaction of the immunoprecipitated protein, and detection of the nascent protein of interest by immunoblotting (39). For nascent protein labeling, HEK293 cells at 80 -90% confluency were incubated in complete normal medium with the indicated dose of PTL or CHX for 1 h. Then HEK293 cells were washed once with warm PBS and incubated with methionine-free medium (Thermo Fisher Scientific) together with PTL or CHX at 37°C for 1 h to deplete methionine reserves.…”

Section: Nonradioactive Metabolic Labeling Assaymentioning

confidence: 99%

The plant sesquiterpene lactone parthenolide inhibits Wnt/β-catenin signaling by blocking synthesis of the transcriptional regulators TCF4/LEF1

Zhu

Yuan

Tian

et al. 2018

Journal of Biological Chemistry

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The Wnt/β-catenin pathway is essential for embryonic development and homeostasis, but excessive activation of this pathway is frequently observed in various human diseases, including cancer. Current therapeutic drugs targeting the Wnt pathway often lack sufficient efficacy, and new compounds targeting this pathway are therefore greatly needed. Here we report that the plant-derived natural product parthenolide (PTL), a sesquiterpene lactone, inhibits Wnt signaling. We found that PTL dose-dependently inhibits Wnt3a- and CHIR99021-induced transcriptional activity assessed with the T-cell factor (TCF)/lymphoid enhancer factor (LEF) firefly luciferase (TOPFlash) assay in HEK293 cells. Further investigations revealed that PTL decreases the levels of the transcription factors TCF4/LEF1 without affecting β-catenin stability or subcellular distribution. Moreover, this effect of PTL on TCF4/LEF1 was related to protein synthesis rather than to proteasome-mediated degradation. Of note, siRNA-mediated knockdown of RPL10, a ribosome protein PTL binds, substantially decreased TCF4/LEF1 protein levels and also Wnt3a-induced TOPFlash activities, suggesting a potential mechanism by which PTL may repress Wnt/β-catenin signaling. In summary, PTL binds RPL10 and thereby potently inhibits the Wnt/β-catenin pathway.

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Small molecule promotes β-catenin citrullination and inhibits Wnt signaling in cancer

Cited by 116 publications

References 48 publications

Proteomic profiling of FBXW7‐mutant serous endometrial cancer cells reveals upregulation of PADI2, a potential therapeutic target

Proteomic profiling of FBXW7‐mutant serous endometrial cancer cells reveals upregulation of PADI2, a potential therapeutic target

Citrullination in Cancer

The plant sesquiterpene lactone parthenolide inhibits Wnt/β-catenin signaling by blocking synthesis of the transcriptional regulators TCF4/LEF1

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