Interaction of tankyrase and peroxiredoxin II is indispensable for the survival of colorectal cancer cells

Dong Hoon Kang,So-Young Lee,Yerin Kim,Eek-Hoon Jho,Ju-Seog Lee,Yukyung Jun,Youngeun Kim,Sanghyuk Lee,Sang Won Kang,Sunmi Lee,Dae-Kee Lee,Doo Jae Lee,Dae-Yeul Yu

doi:10.1038/s41467-017-00054-0

Dong Hoon Kang, So-Young Lee + Show 11 more

Open Access

https://doi.org/10.1038/s41467-017-00054-0

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Journal: Nature Communications	Publication Date: Jun 28, 2017
Citations: 38	License type: open-access

Affiliation: Ewha Womans University, University of Seoul

Abstract

Mammalian 2-Cys peroxiredoxin (Prx) enzymes are overexpressed in most cancer tissues, but their specific signaling role in cancer progression is poorly understood. Here we demonstrate that Prx type II (PrxII) plays a tumor-promoting role in colorectal cancer by interacting with a poly(ADP-ribose) polymerase (PARP) tankyrase. PrxII deletion in mice with inactivating mutation of adenomatous polyposis coli (APC) gene reduces intestinal adenomatous polyposis via Axin/β-catenin axis and thereby promotes survival. In human colorectal cancer cells with APC mutations, PrxII depletion consistently reduces the β-catenin levels and the expression of β-catenin target genes. Essentially, PrxII depletion hampers the PARP-dependent Axin1 degradation through tankyrase inactivation. Direct binding of PrxII to tankyrase ARC4/5 domains seems to be crucial for protecting tankyrase from oxidative inactivation. Furthermore, a chemical compound targeting PrxII inhibits the expansion of APC-mutant colorectal cancer cells in vitro and in vivo tumor xenografts. Collectively, this study reveals a redox mechanism for regulating tankyrase activity and implicates PrxII as a targetable antioxidant enzyme in APC-mutation-positive colorectal cancer.

Highlights

Mammalian 2-Cys peroxiredoxin (Prx) enzymes are overexpressed in most cancer tissues, but their specific signaling role in cancer progression is poorly understood
Numerous studies have indicated that intestinal tumorigenesis initiated by adenomatous polyposis coli (APC) mutations is promoted by the acquired or inherited mutation in the DNA glycosylase enzymes essential for base excision repair of oxidative DNA damage[6], which suggests that elevation of reactive oxygen species (ROS) levels is certainly involved in the APC mutation-driven intestinal tumorigenesis
2-Cys Prxs are ubiquitously expressed in most tissues, including intestines[20], we found that, by examining the expression pattern of Prx isoforms in the Human Proteome Atlas, Prx type II (PrxII) is the most abundant isoform in colorectal cancer (CRC) tissues[21]

Summary

Introduction

Mammalian 2-Cys peroxiredoxin (Prx) enzymes are overexpressed in most cancer tissues, but their specific signaling role in cancer progression is poorly understood. We demonstrate that Prx type II (PrxII) plays a tumor-promoting role in colorectal cancer by interacting with a poly(ADP-ribose) polymerase (PARP) tankyrase. In human colorectal cancer cells with APC mutations, PrxII depletion consistently reduces the β-catenin levels and the expression of β-catenin target genes. This study reveals a redox mechanism for regulating tankyrase activity and implicates PrxII as a targetable antioxidant enzyme in APC-mutation-positive colorectal cancer. More than 50% of patients with colorectal cancer (CRC) have inactivating mutations in the adenomatous polyposis coli (APC) tumor suppressor gene[1]. We found that PrxII absence reduced oncogenic β-catenin in the adenomatous polyps as well as the CRC cell with APC mutations This unexpected result is due to the Axin1-dependent β-catenin degradation enhanced by a H2O2-dependent inactivation of TNKS1 PARP activity in the absence of PrxII.

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