Combinatorial Inhibition of Menin and the Histone Methyltransferase DOT1L as a Novel Therapeutic Strategy for Ovarian Cancer Treatment
Descrizione ProvvisoriaPurpose OC is characterized by a low response rate and high frequency of resistance development to currently available treatments, indicating to an urgent need for the identification of novel and more effective therapies. Several studies demonstrated DOT1L therapeutic potential in OC cells. However, DOT1L inhibitors efficacy and safety still require improvement that may be reached by combination targeting of this epigenetic modifier and its protein co-factors such as menin. Methods We applied siRNA-mediated gene knock-down and pharmacological inhibition coupled to cell proliferation assay on a panel of high grade serous OC cell lines in order to evaluate menin depletion and blockade effect on the proiferation of OC cells. We fully characterized processes,  transcriptionally regulated by menin in chemotherapy-sensitive and resistant OC cells and tested the effect of simultaneous inhibition of menin and DOT1L on proliferation and transcriptional profile in these cells. Results Menin silencing and pharmacological inhibition exert an antiproliferative effect in OC cells and profound impact on transcriptome of PEO1 and PEO4 cells via down-regulation of cell cycle-related genes, aryl hydrocarbon receptor, MYC and KRAS signaling. We demonstrated assoiation of menin and DOT1L in OC cells and exsistence of a subset of genes concordantly regulated by the two proteins. Importantly, we found that simultaneous administration of DOT1L and menin-targeting drugs exerts an additive effect on the growth of chemotherapy-sensitive and -refractory relapsed OC cells driven by profound transcriptome changes related to both menin and DOT1L activities. Conclusions Described in this study results suggest that menin functionally cooperates with DOT1L in OC cells modulating transcription of genes involved in key cellular functions including cell proliferation. Dual inhibition of these two epigenetic regulators may represent a worth exploring mode to further improve the therapy response and survival of OC patients.
Descrizione ProvvisoriaPurpose OC is characterized by a low response rate and high frequency of resistance development to currently available treatments, indicating to an urgent need for the identification of novel and more effective therapies. Several studies demonstrated DOT1L therapeutic potential in OC cells. However, DOT1L inhibitors efficacy and safety still require improvement that may be reached by combination targeting of this epigenetic modifier and its protein co-factors such as menin. Methods We applied siRNA-mediated gene knock-down and pharmacological inhibition coupled to cell proliferation assay on a panel of high grade serous OC cell lines in order to evaluate menin depletion and blockade effect on the proiferation of OC cells. We fully characterized processes,  transcriptionally regulated by menin in chemotherapy-sensitive and resistant OC cells and tested the effect of simultaneous inhibition of menin and DOT1L on proliferation and transcriptional profile in these cells. Results Menin silencing and pharmacological inhibition exert an antiproliferative effect in OC cells and profound impact on transcriptome of PEO1 and PEO4 cells via down-regulation of cell cycle-related genes, aryl hydrocarbon receptor, MYC and KRAS signaling. We demonstrated assoiation of menin and DOT1L in OC cells and exsistence of a subset of genes concordantly regulated by the two proteins. Importantly, we found that simultaneous administration of DOT1L and menin-targeting drugs exerts an additive effect on the growth of chemotherapy-sensitive and -refractory relapsed OC cells driven by profound transcriptome changes related to both menin and DOT1L activities. Conclusions Described in this study results suggest that menin functionally cooperates with DOT1L in OC cells modulating transcription of genes involved in key cellular functions including cell proliferation. Dual inhibition of these two epigenetic regulators may represent a worth exploring mode to further improve the therapy response and survival of OC patients.