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Joo, Hyun-Chel,Choi, Jung-Won,Moon, Hanbyeol,Lee, Chang Youn,Yoo, Kyung-Jong,Kim, Sang Woo,Hwang, Ki-Chul Elsevier 2018 Biochemical and biophysical research communication Vol.499 No.2
<P><B>Abstract</B></P> <P>A previous study showed that small G protein signaling modulator 3 (SGSM3) was highly correlated with Cx43 in heart functions and that high levels of SGSM3 may induce Cx43 turnover through lysosomal degradation in infarcted rat hearts. Here, we investigated the protective effects of kenpaullone on cardiomyocytes following H<SUB>2</SUB>O<SUB>2</SUB>-induced oxidative stress mediated by the interaction of SGSM3 with Cx43. We found that the gap junction protein Cx43 was significantly down-regulated in an H<SUB>2</SUB>O<SUB>2</SUB> concentration-dependent manner, whereas expression of SGSM3 was up-regulated upon H<SUB>2</SUB>O<SUB>2</SUB> exposure in H9c2 cells. The effect of kenpaullone pretreatment on H<SUB>2</SUB>O<SUB>2</SUB>-induced cytotoxicity was evaluated in H9c2 cells. H<SUB>2</SUB>O<SUB>2</SUB> markedly increased the release of lactate dehydrogenase (LDH), while kenpaullone pretreatment suppressed LDH release in H9c2 cells. Moreover, kenpaullone pretreatment significantly reduced ROS fluorescence intensity and significantly down-regulated the level of apoptosis-activating genes (cleaved caspase-3, cleaved caspase-9 and cytochrome C), autophagy markers (LC3A/B), and the Cx43-interacting partner SGSM3. These results suggest that kenpaullone plays a role in protecting cardiomyocytes from oxidative stress and that the turnover of Cx43 through SGSM3-induced lysosomal degradation underlies the anti-apoptotic effect of kenpaullone.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Cx43 was down-regulated in an H<SUB>2</SUB>O<SUB>2</SUB> concentration-dependent manner, whereas SGSM3 was up-regulated in H9c2 cells. </LI> <LI> Kenpaullone pretreatment reduced ROS fluorescence intensity and apoptosis-activating gene levels. </LI> <LI> Kenpaullone plays a role in protecting cardiomyocytes from oxidative stress. </LI> </UL> </P>
Song, Kwon-Ho,Choi, Chel Hun,Lee, Hyo-Jung,Oh, Se Jin,Woo, Seon Rang,Hong, Soon-Oh,Noh, Kyung Hee,Cho, Hanbyoul,Chung, Eun Joo,Kim, Jae-Hoon,Chung, Joon-Yong,Hewitt, Stephen M.,Baek, Seungki,Lee, Kyun American Association for Cancer Research 2017 Cancer Research Vol.77 No.18
<P>These findings link a regulator of cancer stem-like cells to epigenetic silencing events that may improve immunotherapy outcomes.</P><P>Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Immunoediting driven by antigen (Ag)-specific T cells enriches NANOG expression in tumor cells, resulting in a stem-like phenotype and immune resistance. Here, we identify HDAC1 as a key mediator of the NANOG-associated phenotype. NANOG upregulated HDAC1 through promoter occupancy, thereby decreasing histone H3 acetylation on K14 and K27. NANOG-dependent, HDAC1-driven epigenetic silencing of cell-cycle inhibitors CDKN2D and CDKN1B induced stem-like features. Silencing of TRIM17 and NOXA induced immune and drug resistance in tumor cells by increasing antiapoptotic MCL1. Importantly, HDAC inhibition synergized with Ag-specific adoptive T-cell therapy to control immune refractory cancers. Our results reveal that NANOG influences the epigenetic state of tumor cells via HDAC1, and they encourage a rational application of epigenetic modulators and immunotherapy in treatment of NANOG<SUP>+</SUP> refractory cancer types. <I>Cancer Res; 77(18); 5039–53. ©2017 AACR</I>.</P>