Amachi Ryota, Hiasa Masahiro, Teramachi Jumpei, Harada Takeshi, Oda Asuka, Nakamura Shingen, Hanson Derek, Watanabe Keiichiro, Fujii Shiro, Miki Hirokazu, Kagawa Kumiko, Iwasa Masami, Endo Itsuro, Kondo Takeshi, Yoshida Sumiko, Aihara Ken-Ichi, Kurahashi Kiyoe, Kuroda Yoshiaki, Horikawa Hideaki, Tanaka Eiji, Matsumoto Toshio, Abe Masahiro
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.
Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School, Tokushima, Japan.
Oncotarget. 2016 Oct 25;7(43):70447-70461. doi: 10.18632/oncotarget.11927.
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.
骨髓瘤（MM）细胞与破骨细胞相互作用，促进MM生长，同时形成酸性骨病变。在此，我们探讨了MM细胞的酸感应及其在MM细胞对酸性条件反应中的作用。酸性条件激活了MM细胞中的PI3K-Akt信号通路，同时以PI3K抑制可抑制的方式上调pH传感器瞬时受体电位阳离子通道亚家族V成员1（TRPV1）。酸激活的PI3K-Akt信号通路促进转录因子Sp1的核定位，从而触发其靶基因的表达，包括TRPV1和HDAC1。一致地，酸性条件下MM细胞中的组蛋白去乙酰化增强，同时抑制包括DR4在内的多种基因。实际上，酸性条件使DR4基因启动子中的组蛋白H3K9去乙酰化，并减少MM细胞中DR4的表达。然而，抑制HDAC以及Sp1或PI3K能够恢复在酸性条件下受到抑制的MM细胞中DR4的表达。这些结果共同表明，酸在MM细胞中激活TRPV1-PI3K-Akt-Sp1信号通路，同时诱导HDAC介导的基因抑制，并表明在MM细胞中形成了酸感应与PI3K-Akt信号通路之间的正反馈环，导致MM细胞对酸性骨病变产生反应。
