Premium
Epigenetic repression of miR‐375 is the dominant mechanism for constitutive activation of the PDPK 1/ RPS 6 KA 3 signalling axis in multiple myeloma
Author(s) -
Tatekawa Shotaro,
Chinen Yoshiaki,
Ri Masaki,
Narita Tomoko,
Shimura Yuji,
MatsumuraKimoto Yayoi,
Tsukamoto Taku,
Kobayashi Tsutomu,
Kawata Eri,
Uoshima Nobuhiko,
Taki Tomohiko,
Taniwaki Masafumi,
Handa Hiroshi,
Iida Shinsuke,
Kuroda Junya
Publication year - 2017
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.14707
Subject(s) - cancer research , epigenetics , trichostatin a , psychological repression , biology , dna methylation , histone deacetylase inhibitor , microrna , microbiology and biotechnology , histone deacetylase , histone , gene expression , genetics , gene
Summary Cytogenetic/molecular heterogeneity is the hallmark of multiple myeloma ( MM ). However, we recently showed that the serine/threonine kinase PDPK 1 and its substrate RPS 6 KA 3 (also termed RSK 2) are universally active in MM , and play pivotal roles in myeloma pathophysiology. In this study, we assessed involvement of aberrant miR‐375 repression in PDPK 1 overexpression in MM . An analysis of plasma cells from 30 pre‐malignant monoclonal gammopathies of undetermined significance and 73 MM patients showed a significant decrease in miR‐375 expression in patient‐derived plasma cells regardless of the clinical stage, compared to normal plasma cells. Introduction of miR‐375 reduced PDPK 1 expression in human myeloma cell lines ( HMCL s), indicating that miR‐375 is the dominant regulator of PDPK 1 expression. In addition, miR‐375 introduction also downregulated IGF 1R and JAK 2 in HMCL s. CpG islands in the MIR 375 promoter were pathologically hypermethylated in all 8 HMCL s examined and in most of 58 patient‐derived myeloma cells. Treatment with SGI ‐110, a hypomethylating agent, and/or trichostatin A, a histone deacetylase inhibitor, increased miR‐375 expression, but repressed PDPK 1, IGF 1R and JAK 2 in HMCL s. Collectively, these results show the universal involvement of overlapping epigenetic dysregulation for abnormal miR‐375 repression in MM , which is likely to contribute to myelomagenesis and to subsequent myeloma progression by activating oncogenic signalling pathways.