Disruption of Wnt/β-Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human Cells

Abstract

Maintenance of chromosomal ends (telomeres) directly contributes to cancer cell immortalization. The telomere protection enzymes belonging to the tankyrase (Tnks) subfamily of poly(ADP-ribose) polymerases (PARPs) have recently been shown to also control transcriptional response to secreted Wnt signaling molecules. Whereas Tnks inhibitors are currently being developed as therapeutic agents for targeting Wnt-related cancers and as modulators of Wnt signaling in tissue-engineering agendas, their impact on telomere length maintenance remains unclear. Here, we leveraged a collection of Wnt pathway inhibitors with previously unassigned mechanisms of action to identify novel pharmacophores supporting Tnks inhibition. A multifaceted experimental approach that included structural, biochemical, and cell biological analyses revealed two distinct chemotypes with selectivity for Tnks enzymes. Using these reagents, we revealed that Tnks inhibition rapidly induces DNA damage at telomeres and telomeric shortening upon long-term chemical exposure in cultured cells. On the other hand, inhibitors of the Wnt acyltransferase Porcupine (Porcn) elicited neither effect. Thus, Tnks inhibitors impact telomere length maintenance independently of their affects on Wnt/β-catenin signaling. We discuss the implications of these findings for anticancer and regenerative medicine agendas dependent upon chemical inhibitors of Wnt/β-catenin signaling.

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00392-15.

ACKNOWLEDGMENTS

We thank Herwig Schüler (Structural Genomics Consortium, Karolinska Institutet, Stockholm, Sweden), Susan Smith (NYU Langone Medical Center), and Ugur Eskiocak (UT Southwestern Medical Center) for providing reagents and Ilgen Mender and Rubina Tuladhar for technical help. We also thank Jon Bohmann for helpful discussions.

This work was supported, in whole or in part, by National Institutes of Health grants R01CA168761 (L.L.), R01GM053163 (Z.O.), and P50-CA70907 (L.L.); Simmons Cancer Center Support Grant 5P30 CA142543 (J.W.S); Welch Foundation grants I-1665 (L.L.), I-1702 (X.Z.), and I-1596 (C.C.); and Cancer Prevention and Research Institute of Texas grant RP130212 (L.L. and C.C.) and grant RP140661 (X.Z.). X.Z. is a Virginia Murchison Linthicum Scholar in Medical Research at UTSW. J.W.S is the Southland Financial Corporation Distinguished Chair in Geriatric Research. This work was supported by the fund from the Japan Society for the Promotion of Science (JSPS) for the Institutional Program for Young Researcher Overseas Visits (K.Y.). The results in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center, at the Advanced Photon Source. Argonne is operated by University of Chicago Argonne, LLC, for the U.S. Department of Energy Office of Biological and Environmental Research under contract DE-AC02-06CH11357. This work was performed in a space constructed with support from National Institutes of Health grant C06 RR30414.