A vicious cycle between acid sensing and survival signaling in myeloma cells: acid-induced epigenetic alteration.

// Ryota Amachi 1, 2 , Masahiro Hiasa 1, 2, 3 , Jumpei Teramachi 1, 4 , Takeshi Harada 1 , Asuka Oda 1 , Shingen Nakamura 1 , Derek Hanson 1 , Keiichiro Watanabe 1, 2 , Shiro Fujii 1 , Hirokazu Miki 1, 5 , Kumiko Kagawa 1 , Masami Iwasa 1 , Itsuro Endo 1 , Takeshi Kondo 1 , Sumiko Yoshida 1 , Ken-Ichi Aihara 1 , Kiyoe Kurahashi 1 , Yoshiaki Kuroda 6 , Hideaki Horikawa 7 , Eiji Tanaka 2 , Toshio Matsumoto 1, 8 , Masahiro Abe 1 1 Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School, Tokushima, Japan 2 Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School, Tokushima, Japan 3 Department of Biomaterials and Bioengineerings, Tokushima University Graduate School, Tokushima, Japan 4 Department of Histology and Oral Histology, Tokushima University Graduate School, Tokushima, Japan 5 Division of Transfusion Medicine and Cell Therapy, Tokushima University hospital, Tokushima, Japan 6 Department of Hematology and Oncology, RIRBM, Hiroshima University, Hiroshima, Japan 7 Support Center for Advanced Medical Sciences, The University of Tokushima Graduate School, Tokushima, Japan 8 Fujii Memorial Institute for Medical Research Tokushima University Graduate School, Tokushima, Japan Correspondence to: Masahiro Abe, email: masabe@tokushima-u.ac.jp Keywords: multiple myeloma, acidic microenvironment, HDAC, Sp1, DR4 Received: February 24, 2016      Accepted: September 02, 2016      Published: September 10, 2016 ABSTRACT 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.