MMSET stimulates myeloma cell growth through microRNA-mediated modulation of c-MYC.
MMSET stimulates myeloma cell growth through microRNA-mediated modulation of c-MYC.
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多发性骨髓瘤（MM）代表终末分化B细胞的恶性增殖，在许多情况下，这与维持高水平的癌蛋白c-MYC有关。组蛋白甲基转移酶MMSET （WHSC1/NSD2）的过表达，由于t（4;14）染色体易位，促进MM细胞的增殖和染色质的整体变化；然而，MMSET刺激肿瘤形成的确切机制仍不完全清楚。我们发现MMSET通过在转录后水平刺激c-MYC的表达来增强MM细胞的增殖。在t(4;14) MM细胞中进行的microRNA （miRNA）分析实验发现，miR-126*是mmset调控的miRNA，预计会靶向c-MYC mRNA。我们发现miR-126*特异性靶向c-MYC的3 ' -非翻译区（3 ' -UTR），抑制其翻译并导致c-MYC蛋白水平降低。该miRNA的表达足以降低t(4;14) MM细胞的增殖率。染色质免疫沉淀分析显示，MMSET结合miR-126*启动子以及KAP1协同抑制因子和组蛋白去乙酰化酶，并与异染色质修饰相关，其特征是H3K9三甲基化增加，H3乙酰化减少，导致miR-126*抑制。总的来说，这项研究揭示了一种导致c-MYC水平升高和t(4;14) MM增殖增强的新机制，以及其他可能具有高MMSET表达的癌症。
Multiple myeloma (MM) represents the malignant proliferation of terminally differentiated B cells, which, in many cases, is associated with the maintenance of high levels of the oncoprotein c-MYC. Overexpression of the histone methyltransferase MMSET (WHSC1/NSD2), due to t(4;14) chromosomal translocation, promotes the proliferation of MM cells along with global changes in chromatin; nevertheless, the precise mechanisms by which MMSET stimulates neoplasia remain incompletely understood. We found that MMSET enhances the proliferation of MM cells by stimulating the expression of c-MYC at the post-transcriptional level. A microRNA (miRNA) profiling experiment in t(4;14) MM cells identified miR-126* as an MMSET-regulated miRNA predicted to target c-MYC mRNA. We show that miR-126* specifically targets the 3′-untranslated region (3′-UTR) of c-MYC, inhibiting its translation and leading to decreased c-MYC protein levels. Moreover, the expression of this miRNA was sufficient to decrease the proliferation rate of t(4;14) MM cells. Chromatin immunoprecipitation analysis showed that MMSET binds to the miR-126* promoter along with the KAP1 corepressor and histone deacetylases, and is associated with heterochromatic modifications, characterized by increased trimethylation of H3K9 and decreased H3 acetylation, leading to miR-126* repression. Collectively, this study shows a novel mechanism that leads to increased c-MYC levels and enhanced proliferation of t(4;14) MM, and potentially other cancers with high MMSET expression.