Tankyrase inhibitors suppress hepatocellular carcinoma cell growth via modulating the Hippo cascade

Jia, Jiaoyuan; Qiao, Yu; Pilo, Maria G.; Cigliano, Antonio; Liu, Xianqiong; Shao, Zixuan; Calvisi, Diego F.; Chen, Xin

doi:10.1371/journal.pone.0184068

Cited by 38 publications

(43 citation statements)

References 49 publications

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“…At days 4–5, cell proliferation was reduced, while apoptosis significantly elevated along with a drastically decrease of ISCs in Tnks DKO mice, even at day 2 and day 3 after the first tamoxifen administration. This is consistent with a plethora of studies showing that TNKS inhibitors suppress cell proliferation in several cancer cell lines [ 48 – 52 ]. Although inhibition of TNKS activity has been shown to block Apc mutant colorectal cancer development [ 53 , 54 ], we found that the organoids derived from the polys of Villin-Cre ; Apc +/fl mice showed normal cell proliferation and activation of Wnt/β-catenin signaling in the presence of XAV939.…”

Section: Discussionsupporting

confidence: 91%

“…The essential role of TNKSs in the maintenance of intestinal epithelium homeostasis is in agreement of the function of Wnt signaling in promoting cell proliferation and inhibiting apoptosis [ 17 ]. The results from previous studies showed the high effectiveness of TNKS inhibitors in inhibiting various cancer cell proliferation including CRC [ 48 , 51 – 53 ]. However, based on our genetic results and previous pharmacologic results [ 58 ], caution should be taken to the possible toxicity of TNKS inhibitors.…”

Section: Discussionmentioning

confidence: 99%

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Tankyrases maintain homeostasis of intestinal epithelium by preventing cell death

Pan

Chiang

et al. 2018

PLoS Genet

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Lgr5+ intestinal stem cells are crucial for fast homeostatic renewal of intestinal epithelium and Wnt/β-catenin signaling plays an essential role in this process by sustaining stem cell self-renewal. The poly(ADP-ribose) polymerases tankyrases (TNKSs) mediate protein poly-ADP-ribosylation and are involved in multiple cellular processes such as Wnt signaling regulation, mitotic progression and telomere maintenance. However, little is known about the physiological function of TNKSs in epithelium homeostasis regulation. Here, using Villin-creERT2;Tnks1-/-;Tnks2fl/fl (DKO) mice, we observed that loss of TNKSs causes a rapid decrease of Lgr5+ intestinal stem cells and magnified apoptosis in small intestinal crypts, leading to intestine degeneration and increased mouse mortality. Consistently, deletion of Tnks or blockage of TNKS activity with the inhibitor XAV939 significantly inhibits the growth of intestinal organoids. We further showed that the Wnt signaling agonist CHIR99021 sustains the growth of DKO organoids, and XAV939 does not cause growth retardation of Apc-/- organoids. Consistent with the promoting function of TNKSs in Wnt signaling, Wnt/β-catenin signaling is significantly decreased with stabilized Axin in DKO crypts. Together, our findings unravel the essential role of TNKSs-mediated protein parsylation in small intestinal homeostasis by modulating Wnt/β-catenin signaling.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Tankyrases maintain homeostasis of intestinal epithelium by preventing cell death

Pan

Chiang

et al. 2018

PLoS Genet

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“…ARCs and the SAM domain direct tankyrase to regulators of a wide range of biological processes, among which Wnt/β-catenin signaling (Huang et al 2009 ; Mariotti et al 2016 , 2017 ; Yang et al 2016 ), the maintenance and mitotic resolution of telomeres (Smith et al 1998 ; Smith and de Lange 2000 ; Dynek and Smith 2004 ) and glucose metabolism (Chi and Lodish 2000 ; Yeh et al 2007 ; Zhong et al 2016 ) are some of the best-studied. Additional roles of tankyrase include the regulation of mitotic spindle formation (Chang et al 2005 , 2009 ), Hippo signaling (Wang et al 2015 ; Troilo et al 2016 ; Jia et al 2017 ) and emerging functions in the DNA damage response (Nagy et al 2016 ), cell migration (Lupo et al 2016 ), and Notch signaling (Bhardwaj et al 2017 ), to name a few. Proteomics studies and in-silico predictions of tankyrase binders illustrate the diverse cellular functions of tankyrase (Guettler et al 2011 ; Li et al 2017 ; Bhardwaj et al 2017 ).…”

Section: Biological Contextmentioning

confidence: 99%

Solution NMR assignment of the ARC4 domain of human tankyrase 2

et al. 2019

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Tankyrases are poly(ADP-ribose)polymerases (PARPs) which recognize their substrates via their ankyrin repeat cluster (ARC) domains. The human tankyrases (TNKS/TNKS2) contain five ARCs in their extensive N-terminal region; of these, four bind peptides present within tankyrase interactors and substrates. These short, linear segments, known as tankyrase-binding motifs (TBMs), contain some highly conserved features: an arginine at position 1, which occupies a predominantly acidic binding site, and a glycine at position 6 that is sandwiched between two aromatic side chains on the surface of the ARC domain. Tankyrases are involved in a multitude of biological functions, amongst them Wnt/β-catenin signaling, the maintenance of telomeres, glucose metabolism, spindle formation, the DNA damage response and Hippo signaling. As many of these are relevant to human disease, tankyrase is an important target candidate for drug development. With the emergence of non-catalytic (scaffolding) functions of tankyrase, it seems attractive to interfere with ARC function rather than the enzymatic activity of tankyrase. To study the mechanism of ARC-dependent recruitment of tankyrase binders and enable protein-observed NMR screening methods, we have as the first step obtained a full backbone and partial side chain assignment of TNKS2 ARC4. The assignment highlights some of the unusual structural features of the ARC domain.

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“…In breast cancer, AMOTL2 increased LATS kinase activity leading to the suppression of metastasis of tumor cells [23]. Besides, when downregulated, AMOTL2 enhanced tumor cells growth [24], migration and angiogenesis [25] via Hippo pathway in hepatocellular carcinoma. MESRB3 regulates proliferation of MEF cells via enhancing the protein level of p27 [26].…”

Section: Discussionmentioning

confidence: 99%

Integrative analysis of exosomal microRNA-149-5p in lung adenocarcinoma

Tian

Zhou

2020

Preprint

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Background Exosomes play an important role in the regulation of various processes in the tumor microenvironment. In this study, we explored the mechanisms of exosomal miR-149-5p in the pathogenesis of lung adenocarcinoma. Methods Raw GEO data were downloaded and normalized using the R package. Exosomal miRNAs that were found to be significantly expressed were subjected to WGCNA co-expression network analysis. The proliferation, migration and apoptotic abilities of tumor cells were assessed by the MTS, Transwell and apoptosis assays. Univariate and multivariate analyses were performed to identify the independent factors of target genes. Results Results showed that exosomal miR-149-5p was enriched in peripheral serum and tumor cells. The upregulation of exosomal miR-149-5p promoted the growth and migration of tumor cells, and inhibited apoptosis of tumor cells. Notably, target genes of exosomal miR-149-5p, AMOTL2 and MSRB3, were significantly downregulated in lung adenocarcinoma and thus may be considered as independent risk factors of poor survival. In TCGA-LUAD cohort, miR-149-5p was found to be a negative regulator of AMOTL2 and MSRB3 genes.Conclusion Collectively, these results provide novel insights for further mechanistic studies on lung adenocarcinoma.

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Tankyrase inhibitors suppress hepatocellular carcinoma cell growth via modulating the Hippo cascade

Cited by 38 publications

References 49 publications

Tankyrases maintain homeostasis of intestinal epithelium by preventing cell death

Tankyrases maintain homeostasis of intestinal epithelium by preventing cell death

Solution NMR assignment of the ARC4 domain of human tankyrase 2

Integrative analysis of exosomal microRNA-149-5p in lung adenocarcinoma

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