A vicious cycle between acid sensing and survival signaling in myeloma cells: acid-induced epigenetic alteration.
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.
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.|Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School, Tokushima, Japan.
Ryota
R
Amachi
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.|Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School, Tokushima, Japan.|Department of Biomaterials and Bioengineerings, Tokushima University Graduate School, Tokushima, Japan.
Masahiro
M
Hiasa
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.|Department of Histology and Oral Histology, Tokushima University Graduate School, Tokushima, Japan.
Jumpei
J
Teramachi
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.
Takeshi
T
Harada
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.
Asuka
A
Oda
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.
Shingen
S
Nakamura
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.
Derek
D
Hanson
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.|Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School, Tokushima, Japan.
Keiichiro
K
Watanabe
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.
Shiro
S
Fujii
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.|Division of Transfusion medicine and cell therapy, Tokushima University hospital, Tokushima, Japan.
Hirokazu
H
Miki
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.
Kumiko
K
Kagawa
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.
Masami
M
Iwasa
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.
Itsuro
I
Endo
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.
Takeshi
T
Kondo
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.
Sumiko
S
Yoshida
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.
Ken-Ichi
KI
Aihara
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.
Kiyoe
K
Kurahashi
Department of Hematology and Oncology, RIRBM, Hiroshima University, Hiroshima, Japan.
Yoshiaki
Y
Kuroda
Support Center for Advanced Medical Sciences, the University of Tokushima Graduate School, Tokushima, Japan.
Hideaki
H
Horikawa
Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School, Tokushima, Japan.
Eiji
E
Tanaka
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.|Fujii Memorial Institute for Medical Research Tokushima University Graduate School, Tokushima, Japan.
Toshio
T
Matsumoto
Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan.
Masahiro
M
Abe
D000143:Acids / Q000737:chemistry*; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
D000143:Acids; D006657:Histones; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D016329:Sp1 Transcription Factor; C105190:TNFRSF10A protein, human; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
DR4; HDAC; Sp1; acidic microenvironment; multiple myeloma