Epigenetic repression of miR‐375 is the dominant mechanism for constitutive activation of the <scp>PDPK</scp>1/<scp>RPS</scp>6<scp>KA</scp>3 signalling axis in multiple myeloma

<jats:title>Summary</jats:title><jats:p>Cytogenetic/molecular heterogeneity is the hallmark of multiple myeloma (<jats:styled-content style="fixed-case">MM</jats:styled-content>). However, we recently showed that the serine/threonine kinase <jats:styled-content style="fixed-case">PDPK</jats:styled-content>1 and its substrate <jats:styled-content style="fixed-case">RPS</jats:styled-content>6<jats:styled-content style="fixed-case">KA</jats:styled-content>3 (also termed <jats:styled-content style="fixed-case">RSK</jats:styled-content>2) are universally active in <jats:styled-content style="fixed-case">MM</jats:styled-content>, and play pivotal roles in myeloma pathophysiology. In this study, we assessed involvement of aberrant miR‐375 repression in <jats:styled-content style="fixed-case">PDPK</jats:styled-content>1 overexpression in <jats:styled-content style="fixed-case">MM</jats:styled-content>. An analysis of plasma cells from 30 pre‐malignant monoclonal gammopathies of undetermined significance and 73 <jats:styled-content style="fixed-case">MM</jats:styled-content> 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 <jats:styled-content style="fixed-case">PDPK</jats:styled-content>1 expression in human myeloma cell lines (<jats:styled-content style="fixed-case">HMCL</jats:styled-content>s), indicating that miR‐375 is the dominant regulator of <jats:styled-content style="fixed-case">PDPK</jats:styled-content>1 expression. In addition, miR‐375 introduction also downregulated <jats:styled-content style="fixed-case">IGF</jats:styled-content>1R and <jats:styled-content style="fixed-case">JAK</jats:styled-content>2 in <jats:styled-content style="fixed-case">HMCL</jats:styled-content>s. CpG islands in the <jats:italic><jats:styled-content style="fixed-case">MIR</jats:styled-content>375</jats:italic> promoter were pathologically hypermethylated in all 8 <jats:styled-content style="fixed-case">HMCL</jats:styled-content>s examined and in most of 58 patient‐derived myeloma cells. Treatment with <jats:styled-content style="fixed-case">SGI</jats:styled-content>‐110, a hypomethylating agent, and/or trichostatin A, a histone deacetylase inhibitor, increased miR‐375 expression, but repressed <jats:styled-content style="fixed-case">PDPK</jats:styled-content>1, <jats:styled-content style="fixed-case">IGF</jats:styled-content>1R and <jats:styled-content style="fixed-case">JAK</jats:styled-content>2 in <jats:styled-content style="fixed-case">HMCL</jats:styled-content>s. Collectively, these results show the universal involvement of overlapping epigenetic dysregulation for abnormal miR‐375 repression in <jats:styled-content style="fixed-case">MM</jats:styled-content>, which is likely to contribute to myelomagenesis and to subsequent myeloma progression by activating oncogenic signalling pathways.</jats:p>