Prof. Toshiki Watanabe and his group have published a paper in Cancer Cell. Constitutive NF-kB activation has causative roles in adult T cell leukemia (ATL) caused by HTLV-1 and other cancers. They for the first time discovered a pathway involving Polycomb-mediated miRNA silencing and NF-kB activation. They studied expression profiles of microRNAs, small functional RNA that target mRNA and regulate gene expression, using tumor cells of ATL. They revealed miR-31 loss in primary ATL cells. miR-31 negatively regulates the noncanonical NF-kB pathway by targeting NF-kB inducing kinase (NIK). NF-kB signal plays important roles in tumor cell growth and resistance to apoptosis, and also in regulation of immunological responses. Loss of miR-31 therefore triggers oncogenic signaling. In ATL cells, miR-31 level is epigenetically regulated, and aberrant upregulation of
Polycomb proteins contribute to miR-31 downregulation in an epigenetic fashion, leading to activation of NF-kB and apoptosis resistance. Introduction of miR-31 into ATL cells resulted in tumor cell death, suggesting a clinical application of miR-31. Furthermore, this emerging circuit operates in other cancers and receptor-initiated NF-kB cascade. Our findings provide a perspective involving the epigenetic program, inflammatory responses, and oncogenic signaling.
The significance of these findings is summarized as follows. They proposed a molecular perspective of the onset of oncogenic signaling. NIK overexpression is a major driving force for constitutive NF-kB activation in various types of cancers. Using ATL cells as a model of NF-kB-addiction, we identified miR-31 as a suppressor of NIK that is completely silenced in ATL cells. Furthermore, an oncogenic function of a subset of Polycomb is implicated in NF-kB signaling via miRNA regulation. This study introduces a fundamental link between the Polycomb-mediated epigenetic regulation and the NF-kB signaling, allowing us to attribute the constitutive activation of NF-kB to epigenetic reprogramming.
Authors: Makoto Yamagishi, Kazumi Nakano, Ariko Miyake, Tadanori Yamochi, Yayoi Kagami, Akihisa Tsutsumi, Yuka Matsuda, Aiko Sato-Otsubo, Satsuki Muto, Atae Utsunomiya, Kazunari Yamaguchi, Kaoru Uchimaru, Seishi Ogawa, and Toshiki Watanabe
Title of the paper: Polycomb-Mediated Loss of miR-31 Activates NIK-Dependent NF-κB Pathway in Adult T Cell Leukemia and Other Cancers
Journal: Cancer Cell 21, 121–135, January 17, 2012
Prof. Toshiki Watanabe
Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo
Address: 4-6-1 Shirokanedai, Minato-ku, Tokyo, Japan. 108-8639 Phone:03-5449-5298