A vicious cycle between acid sensing and survival signaling in myeloma cells: acid-induced epigenetic alteration.
A vicious cycle between acid sensing and survival signaling in myeloma cells: acid-induced epigenetic alteration.
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DOI：
10.18632/oncotarget.11927
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发表时间：
2016-10-25
期刊：
影响因子：
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通讯作者：
Abe M
中科院分区：
文献类型：
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作者：
Amachi R;Hiasa M;Teramachi J;Harada T;Oda A;Nakamura S;Hanson D;Watanabe K;Fujii S;Miki H;Kagawa K;Iwasa M;Endo I;Kondo T;Yoshida S;Aihara KI;Kurahashi K;Kuroda Y;Horikawa H;Tanaka E;Matsumoto T;Abe M
骨髓瘤（MM）细胞和破骨细胞相互作用，以促进MM生长，同时产生酸性骨病变。在这里，我们探讨了MM细胞的酸敏感及其在MM细胞对酸性条件的反应中的作用。酸性条件激活MM细胞中的PI 3 K-Akt信号传导，同时以可通过PI 3 K抑制的方式上调pH传感器瞬时受体电位阳离子通道亚家族V成员1（TRPV 1）。酸激活的PI 3 K-Akt信号促进转录因子Sp1的核定位，以触发其靶基因的表达，包括TRPV 1和HDAC 1。一致地，组蛋白去乙酰化在酸性条件下在MM细胞中增强，同时抑制多种基因，包括DR 4。事实上，酸性条件使DR 4基因启动子中的组蛋白H3 K9脱乙酰化并减少MM细胞中的DR 4表达。然而，HDAC以及Sp1或PI 3 K的抑制能够恢复在酸性条件下抑制的MM细胞中的DR 4表达。这些结果共同表明，酸激活MM细胞中的TRPV 1-PI 3 K-Akt-Sp1信号传导，同时诱导HDAC介导的基因抑制，并表明在MM细胞中形成酸感应和PI 3 K-Akt信号传导之间的正反馈回路，导致MM细胞对酸性骨病变的反应。
Myeloma (MM) cells and osteoclasts are mutually interacted to enhance MM growth while creating acidic bone lesions. Here, we explored acid sensing of MM cells and its role in MM cell response to acidic conditions. Acidic conditions activated the PI3K-Akt signaling in MM cells while upregulating the pH sensor transient receptor potential cation channel subfamily V member 1 (TRPV1) in a manner inhibitable by PI3K inhibition. The acid-activated PI3K-Akt signaling facilitated the nuclear localization of the transcription factor Sp1 to trigger the expression of its target genes, including TRPV1 and HDAC1. Consistently, histone deacetylation was enhanced in MM cells in acidic conditions, while repressing a wide variety of genes, including DR4. Indeed, acidic conditions deacetylated histone H3K9 in a DR4 gene promoter and curtailed DR4 expression in MM cells. However, inhibition of HDAC as well as either Sp1 or PI3K was able to restore DR4 expression in MM cells suppressed in acidic conditions. These results collectively demonstrate that acid activates the TRPV1-PI3K-Akt-Sp1 signaling in MM cells while inducing HDAC-mediated gene repression, and suggest that a positive feedback loop between acid sensing and the PI3K-Akt signaling is formed in MM cells, leading to MM cell response to acidic bone lesions.