Tankyrases maintain homeostasis of intestinal epithelium by preventing cell death

Pan, Ye; Chiang, Y. Jeffrey; Qi, Zhengjian; Li, Yehua; Wang, Shan; Liu, Yuan; Li, Xintong; Chen, Ye-Guang

doi:10.1371/journal.pgen.1007697

Cited by 10 publications

(6 citation statements)

References 60 publications

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“…A number of small-molecule inhibitors have been reported to target β-catenin, including PRI-724 that disrupts the β-catenin-CBP interaction 7 , PNU-74654 that disrupts the β-catenin/TCF interaction 7 and MSAB that promotes β-catenin degradation 9 . We compared the inhibitory effect of xStAx-VHLL with those inhibitors as well as XAV939 that inhibits tankyrases and thus stabilizes Axin 23,24 . As shown in Fig.…”

Section: Design Of Protac β-Catenin Degradersmentioning

confidence: 99%

A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer

et al. 2020

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Aberrant activation of Wnt/β-catenin signaling has been associated with the onset and progression of many types of tumors and thus β-catenin represents one attractive intracellular target for cancer therapy. Based on the Axin-derived peptide that binds to β-catenin, two stapled peptides SAHPA1 and xStAx were reported to enhance or impair Wnt/ β-catenin signaling, respectively. In this study, we designed PROTACs (proteolysis targeting chimeras) by coupling SAHPA1 or xStAx with the VHL ligand to achieve efficient β-catenin degradation. The obtained xStAx-VHLL sustained β-catenin degradation and manifested strong inhibition of Wnt signaling in cancer cells and in APC −/− organoids. Furthermore, xStAx-VHLL could effectively restrain tumor formation in BALB/C nude mice, and diminish the existing tumors in APC min/+ mice. More importantly, xStAx-VHLL could potently inhibit the survival of colorectal cancer patientderived organoids. These findings suggest that xStAx-VHLL exhibits the ability of cancer prevention and cure, highlighting the potential of β-catenin degrader PROTACs as a new class of promising anticancer agent.

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Section: Design Of Protac β-Catenin Degradersmentioning

confidence: 99%

A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer

et al. 2020

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“…Unlike other PARP proteins, they play no role in DNA repair, but rather potentiate WNT signaling by PARylating AXIN1/2, targeting it for degradation, and decreasing the stability and activity of the DC (7)(8)(9). Numerous small molecules that enable selective TNKS1/2 blockade and WNT pathway suppression in CRC cell lines (10)(11)(12) and normal mouse intestine (13,14) have been described, yet evidence for suppression of WNT-driven tumor growth in vivo is conflicting (15)(16)(17). Thus, it is unclear if, and in what context, re-engaging the tumor suppressive DC is an effective approach to control hyperactive WNT/β-catenin signaling.…”

Section: Introductionmentioning

confidence: 99%

Distinct Colorectal Cancer–Associated APC Mutations Dictate Response to Tankyrase Inhibition

et al. 2019

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The majority of colorectal cancers (CRCs) show hyperactivated WNT signaling due to inactivating mutations in the APC tumor suppressor. Genetically restoring Apc suppresses WNT and induces rapid and sustained tumor regression, implying that re-engaging this endogenous tumor suppressive mechanism may be an effective therapeutic strategy. Here, using new animal models, human cell lines, and ex vivo organoid cultures, we show that Tankyrase (TNKS) inhibition can control WNT hyperactivation and provide long-term tumor control in vivo, but that effective responses are critically dependent on how APC is disrupted. Mutant APC proteins truncated within the Mutation Cluster Region (MCR) region physically engage the destruction complex and suppress the WNT transcriptional program, while early APC truncations (i.e. Apc Min) show limited interaction with AXIN1 and β-catenin, and do not respond to TNKS blockade. Together, this work shows that TNKS inhibition, like APC restoration, can reestablish endogenous control of WNT/β-catenin signaling, but that APC genotype is a crucial determinant of this response.

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“…Due to its strong mitogenic activity, several mechanisms have evolved to maintain Wnt/β-catenin signaling under tight control. Multiple inhibitors operating at different levels of the Wnt/β-catenin signaling cascade, including Axin 97 and SH3 domain-binding protein 4 (SH3BP4) 98 , contribute to maintaining intestinal homeostasis. However, it seems that the main feedback mechanism ensuring adequate levels of Wnt signaling in the intestinal crypt occurs at the plasma membrane.…”

Section: Rnf43 and Znrf3 Are Fundamental Feedback Inhibitors Of Wnt S...mentioning

confidence: 99%

Clone wars: From molecules to cell competition in intestinal stem cell homeostasis and disease

2022

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The small intestine is among the fastest self-renewing tissues in adult mammals. This rapid turnover is fueled by the intestinal stem cells residing in the intestinal crypt. Wnt signaling plays a pivotal role in regulating intestinal stem cell renewal and differentiation, and the dysregulation of this pathway leads to cancer formation. Several studies demonstrate that intestinal stem cells follow neutral drift dynamics, as they divide symmetrically to generate other equipotent stem cells. Competition for niche space and extrinsic signals in the intestinal crypt is the governing mechanism that regulates stemness versus cell differentiation, but the underlying molecular mechanisms are still poorly understood, and it is not yet clear how this process changes during disease. In this review, we highlight the mechanisms that regulate stem cell homeostasis in the small intestine, focusing on Wnt signaling and its regulation by RNF43 and ZNRF3, key inhibitors of the Wnt pathway. Furthermore, we summarize the evidence supporting the current model of intestinal stem cell regulation, highlighting the principles of neutral drift at the basis of intestinal stem cell homeostasis. Finally, we discuss recent studies showing how cancer cells bypass this mechanism to gain a competitive advantage against neighboring normal cells.

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Tankyrases maintain homeostasis of intestinal epithelium by preventing cell death

Cited by 10 publications

References 60 publications

A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer

A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer

Distinct Colorectal Cancer–Associated APC Mutations Dictate Response to Tankyrase Inhibition

Clone wars: From molecules to cell competition in intestinal stem cell homeostasis and disease

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