TY - JOUR
T1 - A vicious cycle between acid sensing and survival signaling in myeloma cells
T2 - Acid-induced epigenetic alteration
AU - Amachi, Ryota
AU - Hiasa, Masahiro
AU - Teramachi, Jumpei
AU - Harada, Takeshi
AU - Oda, Asuka
AU - Nakamura, Shingen
AU - Hanson, Derek
AU - Watanabe, Keiichiro
AU - Fujii, Shiro
AU - Miki, Hirokazu
AU - Kagawa, Kumiko
AU - Iwasa, Masami
AU - Endo, Itsuro
AU - Kondo, Takeshi
AU - Yoshida, Sumiko
AU - Aihara, Ken ichi
AU - Kurahashi, Kiyoe
AU - Kuroda, Yoshiaki
AU - Horikawa, Hideaki
AU - Tanaka, Eiji
AU - Matsumoto, Toshio
AU - Abe, Masahiro
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Acidic microenvironment
KW - DR4
KW - HDAC
KW - Multiple myeloma
KW - Sp1
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U2 - 10.18632/oncotarget.11927
DO - 10.18632/oncotarget.11927
M3 - Article
C2 - 27626482
AN - SCOPUS:84994338853
SN - 1949-2553
VL - 7
SP - 70447
EP - 70461
JO - Oncotarget
JF - Oncotarget
IS - 43
ER -