Characterization of a SUMO Ligase that is Essential for DNA Damage- Induced-NF-kB Activation

摘要

It has been recently proposed that inhibition of NF-kB may be a therapeutic target for the treatment of ER- breast cancers. As of now, the majority of NF-kB inhibitors focus on the key signal integrating complex known as the IkB kinase (IKK) complex. Since NF-kB plays a major role in many essential physiological processes in the cell, global inhibition of NF-kB at the central IKK complex could allow for increased risk of side effects as well as the desirable effects on cancer cell death. Hence, identification of specific, novel molecular targets in the NF-kB signaling pathway may lead to the identification of more specific NF-kB inhibitors. Our hypothesis is that PIASy, a SUMO ligase, is essential for DNA damage induced NF-kB activation, however is not critical for classical activation of NF-kB, leaving the more physiological pathway intact. We reveal that PIASy is signaling at the level of NEMO SUMOylation, a posttranslational modification that we recently identified being critical for DNA damage induced activation of NF-kB. Reduction of PIASy through siRNA caused inhibition of NF-kB in response to multiple DNA damaging agents commonly used in anti-cancer therapy. We provide strong evidence that PIASy is working at the level of NEMO SUMOylation and propose that PIASy is the SUMO ligase for NEMO. Furthermore, we show that the catalytic activity of PIASy is essential for NF-kB activation and hence suggest that inhibition of PIASy may be used as a more specific inhibitor in anti-cancer therapy to treat ER- breast cancer.