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Abstract:

Aberrant Wnt/尾-catenin signaling drives tumorigenesis and metastasis of many cancers. Catalytic inhibition of tankyrase suppresses Wnt/尾-catenin signaling by blocking the turnover of Axin that helps assemble the 尾-catenin destruction complex (DC). However, tankyrase also supports Wnt/尾-catenin signaling through a poorly understood mechanism of molecular scaffolding. Herein, we show that catalytic inhibition of tankyrase induces tankyrase accumulation to augment Axin puncta formation. This event drives a liquid-to-solid phase transition of the DC to impede the turnover of 尾-catenin, which potentially explains the unsatisfactory outcomes of drugging the Wnt/尾-catenin signaling pathway by TNKSi. By contrast, depleting tankyrase with PROTAC dissolves the Axin puncta without affecting the DC function. As such, it allows for a deep suppression of the Wnt/尾-catenin pathway activity and provides a better control of the proliferation of cancer cells with dysfunctional APC mutations. Collectively, induced degradation of tankyrase is a promising new approach to treat cancers driven by 尾-catenin.

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Bio:

Chuo Chen was born and grew up in Taipei, Taiwan, ROC. He studied natural product synthesis under the direction of Professor Matthew Shair at Harvard University and obtained his Ph.D. degree in 2001. He then worked as a Howard Hughes Medical Institute postdoctoral fellow in Professor Stuart Schreiber's laboratory at Harvard University before joining the faculty of the University of Texas Southwestern Medical Center in 2004. He is now a Professor in Biochemistry and a Southwestern Medical Foundation Scholar in Biomedical Research. Chuo has diverse interests in chemical and biological researches. His early career focuses on natural product synthesis and synthetic method development. Currently, his lab uses a combination of chemical and biological tools to study the cGAS-STING and Wnt signaling pathways.