Abstract 1882: Tankyrase-binding protein TNKS1BP1 regulates cancer cell invasion

Abstract

Abstract Tankyrase, a member of poly(ADP-ribose) polymerase (PARP) family, catalyzes addition of long PAR chains onto the acceptor proteins, such as TRF1, a telomere-binding protein, and Axin, a repressor of Wnt/β-catenin signaling. Tankyrase-mediated PARylation of TRF1 and Axin represses the biological functions of these proteins, leading to enhanced telomere elongation by telomerase and upregulation of Wnt/β-catenin signaling, respectively. Thus, tankyrase is a multifunctional protein that supports oncogenic properties of cancer cells. Given that tankyrase has a large protein-protein interaction platform called ANK repeat clusters, and is broadly distributed to various intracellular loci, including telomeres, nucleoplasm, nuclear pore complexes, cytoplasm, Golgi, and spindle poles, this protein seems to have a yet unidentified function. In the present study, we explored the function of a novel tankyrase-binding protein called TNKS1BP1 and elucidated its contribution to regulating cancer cell invasion. Since TNKS1BP1 co-localizes with the actin filaments, we first examined the effect of genetic manipulation of TNKS1BP1 expression on cell invasion. We found that TNKS1BP1 depletion by small interfering RNAs increased the invasive capacity of human fibrosarcoma cells, whereas its overexpression decreased the cell invasion. In TNKS1BP1-depleted cells, actin filament dynamics, focal adhesion and lamellipodia ruffling were increased with activation of the ROCK-LIMK-cofilin pathway, which promotes cell motility. Importantly, tankyrase overexpression reproduced the phenotype of TNKS1BP1-depleted cells and enhanced cell invasion in a PARP activity-dependent manner. Under approval by Institutional Review Board of Japanese Foundation for Cancer Research, we performed immunohistochemical analysis of clinical pancreatic cancer. We found that TNKS1BP1 protein expression is decreased in invasive regions of the tumors. Taken together, these observations suggest that the tankyrase-TNKS1BP1 axis constitutes a post-translational modulator of cell invasion and its aberration promotes cancer malignancy. Citation Format: Tomokazu Ohishi, Haruka Yoshida, Masamichi Katori, Toshiro Migita, Yukiko Muramatsu, Mao Miyake, Yuichi Ishikawa, Akio Saiura, Shun-ichiro Iemura, Tohru Natsume, Hiroyuki Seimiya. Tankyrase-binding protein TNKS1BP1 regulates cancer cell invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1882. doi:10.1158/1538-7445.AM2017-1882