Abstract
Tumor suppressive microRNA (miR)-150 inhibits metastasis by combining with the C-C chemokine receptor 6 (CCR6) “seed sequence” mRNA of the 3′-untranslated region (3′-UTR) in advanced cutaneous T-cell lymphoma (CTCL). Because the histone deacetylase inhibitor (HDACI) vorinostat showed excellent outcomes for treating advanced CTCL, HDACIs may reduce the metastasis of CTCL by targeting miR-150 and/ or CCR6. To examine whether these candidate molecules are essential HDACI targets in advanced CTCL, we used the My-La, HH, and HUT78 CTCL cell lines for functional analysis because we previously demonstrated that their xenografts in NOD/Shi-scid IL-2γnul mice (CTCL mice) induced multiple metastases. We found that pan- HDACIs (vorinostat and panobinostat) inhibited the migration of CTCL cells and downregulated CCR6. The miRNA microarray analysis against CTCL cell lines demonstrated that these pan-HDACIs commonly upregulated 161 miRNAs, including 34 known tumor suppressive miRNAs such as miR-150. Although 35 miRNAs possessing the CCR6 “seed sequence” were included in these 161 miRNAs, miR-150 and miR-185-5p were downregulated in CTCL cells compared to in normal CD4+ T-cells. The transduction of 12 candidate miRNAs against CTCL cells revealed that miR-150 most efficiently inhibited their migration capabilities and downregulated CCR6. Quantitative reverse transcriptase-polymerase chain reaction demonstrated that miR-150 was downregulated in advanced but not early CTCL primary cases. Finally, we injected miR-150 or siCCR6 into CTCL mice and found that mouse survival was significantly prolonged. These results indicate that miR-150 and its target, CCR6, are essential therapeutic targets of pan-HDACIs in advanced CTCL with metastatic potential.
Highlights
Cutaneous T-cell lymphoma (CTCL) mainly comprises mycosis fungoides (MF) and Sezary syndrome (SzS) [1,2,3]
We found that pan- histone deacetylase inhibitor (HDACI) inhibited the migration of cutaneous T-cell lymphoma (CTCL) cells and downregulated chemokine receptor 6 (CCR6)
To determine whether the HDACIs [pan-HDACIs and Class I-specific HDACI, romidepsin] affected the expression of CCR6, we examined the expression of CCR6 by qRT-PCR and western blotting analyses of CTCL cell lines treated with the respective HDACI
Summary
Cutaneous T-cell lymphoma (CTCL) mainly comprises mycosis fungoides (MF) and Sezary syndrome (SzS) [1,2,3]. Between the early and advanced stages of MF, additional genetic or epigenetic alterations may occur and likely contribute to MF progression and aggressive clinical behavior. These alterations could involve coding or noncoding genes or both including microRNA (miRNA), which are a class of small non-coding regulatory RNA molecules that pair with the 3′-untranslated region (UTR) of target messenger RNAs to repress their translation [4, 5]. We previously demonstrated that the expression level of miR-150 was suppressed in both T/NK cell lymphoma [9] and advanced CTCL [10]. Because there is no current report on genomic alteration of the miR-150 region and no mutation is evident in the pre-miRNA-150 gene [11], we suspected that epigenetic mechanisms such as the activation of histone deacetylases might be responsible for repressing miR-150 expression in advanced CTCL
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