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

Ryota Amachi, Masahiro Hiasa, Jumpei Teramachi, Takeshi Harada, Asuka Oda, Shingen Nakamura, Derek Hanson, Keiichiro Watanabe, Shiro Fujii, Hirokazu Miki, Kumiko Kagawa, Masami Iwasa, Itsuro Endo, Takeshi Kondo, Sumiko Yoshida, Ken ichi Aihara, Kiyoe Kurahashi, Yoshiaki Kuroda, Hideaki Horikawa, Eiji TanakaToshio Matsumoto, Masahiro Abe

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)70447-70461
Number of pages15
JournalOncotarget
Volume7
Issue number43
DOIs
Publication statusPublished - 2016
Externally publishedYes

Keywords

  • Acidic microenvironment
  • DR4
  • HDAC
  • Multiple myeloma
  • Sp1

ASJC Scopus subject areas

  • Oncology

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