BHC80 is Critical in Suppression of Snail-LSD1 Interaction and Breast Cancer Metastasis

摘要

By using a tandem affinity-mass spectrometry coupled analysis, we identified Snail-interacting proteins including LSD1, BHC80 and PARP1. Based on our preliminary data, Snail uses its highly conserved SNAG domain to recruit LSD1 to its target gene promoter for transcription repression. Among the Snail- interacting proteins, PARP1 is critical in regulating the protein stability of Snail and LSD1, as well as Snail/LSD1 binding to the target gene promoter area. According to the modified Statement of Work, we focused on clarifying the mechanism of PARP1-mediated cancer development. We demonstrated that Snail cooperates with LSD1 to repress PTEN in a PARP1-dependent manner. Upon doxorubicin treatment, Snail becomes tightly associated with PARP1 through its pADPrbinding motif and is subject to poly(ADP-ribosyl)ation. This modification can enhance Snail-LSD1 interaction and promote the recruitment of LSD1 to PTEN promoter, where LSD1 removes methylation on histone H3 lysine 4 for transcription repression. Furthermore, treatment of tumor cells with PARP1 inhibitor AZD2281 can compromise doxorubicin-induced PTEN suppression and enhance the inhibitory effect of doxorubicin. Together, we proposed a tentative drug-resistant mechanism through which tumor cells defend themselves against DNA damage-induced apoptosis. PARP1 inhibitors in combination with DNA damaging reagents might represent a promising treatment strategy targeting tumors with over-activated Snail and LSD1. We submitted the manuscript to Cell Cycle, and the paper was accepted for publication in March 2014. We are currently continuing to characterize other Snail-interacting proteins to get a clearer picture of Snail-mediated cancer progression.