BHC80 is Critical in Suppression of Snail-LSD1 Interaction and Breast Cancer Metastasis
Annual summary 1 Jan 2012-31 Dec 2012
KENTUCKY UNIV LEXINGTON
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As mentioned in the previous annual report, in addition to BHC80, we identified PARP1 as a component of SnailLSD1. According to our preliminary data, PARP1 is critical in regulating the protein stability of Snail and LSD1, as well as SnailLSD1 binding to the target gene promoter. In the current report, we further showed that doxorubicin treatment can enhance Snail-LSD1 interaction in a PARP1-dependent manner. In addition, Snail contains a potential pADPr-binding motif and is subject to polyADP-ribosylation. Our data also suggested that the enzymatic activity of PARP1 is required for Snail-LSD1 binding to the PTEN promoter upon binding, LSD1 demethylates histone H3 lysine 4 at the promoter region in favor of PTEN transcription suppression and the downstream Akt phosphorylation. Furthermore, we found that PARP1 inhibitor AZD2281 can enhance the killing effect of doxorubicin on selective breast and colon cancer cells. Together, we proposed a new mechanism adopted by cancer cells to defend themselves against DNA damage-induced apoptosis, which gives us new implications on the design of efficient cancer treatment strategies. We will continue to characterize other Snail-interacting proteins to get a clearer picture of Snail-mediated cancer progression.
- Anatomy and Physiology
- Medicine and Medical Research