Myc represses miR-15a/miR-16-1 expression through recruitment of HDAC3 in mantle cell and other non-Hodgkin B-cell lymphomas

Abstract

Our recent study demonstrated miR-15a/16-1 downregulation in mantle cell lymphoma (MCL). Here, we investigated mechanisms of miR-15a/16-1 transcriptional repression and its epigenetic regulation by c-Myc and histone deacetylase (HDAC) in MCL. c-Myc expression was detected in MCL cell lines and in the primary MCL samples, and pri-miR-15a/16-1 mRNAs were significantly upregulated in Mino and Jeko-1 cells with c-Myc knockdown by small interfering RNAs (siRNAs). Our co-immunoprecipitation analysis showed that c-Myc interacted with HDAC3. Moreover, using chromatin immunoprecipitation, we demonstrated that both c-Myc and HDAC3 co-localized to the two promoters of the miR-15a/16-1 cluster gene, DLEU2, and inhibition of HDAC3 increased histone acetylation of the DLEU2 promoters. Luciferase reporter assay confirmed the dependence of Myc-mediated DLEU2 transcriptional repression on HDAC3. Treatment with the pan-HDAC inhibitor, suberoylanilide hydroxamic acid and HDAC3 siRNA resulted in increased miR-15a/16-1 expression. The regulatory mechanism of miR-15a/16-1 was further demonstrated in Burkitt lymphoma and Myc overexpressing cell lines. These findings highlight the role of HDAC3 in Myc-induced miR-15a/16-1 changes and reveal novel mechanisms for c-Myc-driven microRNA suppression and malignant transformation in aggressive B-cell malignancies.

A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas

“…Conversely, we demonstrate that miR-548m regulated c-Myc expression through direct targeting of c-Myc 3′-UTR and downregulation of miR-548m, in turn, contributes to c-Myc overexpression, thus generating a positive c-Myc/miR-548m feedback loop to ensure persistent high protein levels of c-Myc and further repression of miR-548m expression in lymphoma microenvironment. Moreover, the finding of c-Myc-induced EZH2-mediated miR-548m repression is in line with findings of our previous study that miR-29 expression is c-Myc and EZH2 dependent, implicating a genetic silencing mechanism for c-Myc-induced widespread miRNA repression (20,21,43). JQ1 functions as a specific inhibitor of BET proteins, including bromodomain-containing protein 4 (BRD4) and BRD2 through interference with the acetyl-lysine recognition domains (bromodomains).…”

“…We next investigated the underlying molecular mechanism of stroma-mediated miR-548m downregulation. Our recent studies revealed that c-Myc recruited HDAC3 and EZH2, a histone methyltransferase and a member of the polycomb group of proteins, to the promoters of miR-29 and miR-15a/16 as corepressors to downregulate miRNA expression (20,21). We, thus, tested whether miR-548m expression is c-Myc dependent and its repression is mediated through histone modification.…”

Identification of Direct Targets of FUSCA3, a Key Regulator of Arabidopsis Seed Development

“…Very few direct interactions between transcriptional regulators and pri-miRNAencoding genes have been reported in plants or other organisms. In animals, there are some reports of transcription factors directly associating with pri-miRNA genes and resulting in the expression or repression of the associated genes (Hino et al, 2008;Xiong et al, 2009;Zhou et al, 2010;Zhang et al, 2012b). In Arabidopsis and other angiosperms, miR156 and miR172 are regulators of phase transitions, with miR156 delaying phase transitions while miR172 promotes the progression through the life cycle (for review, see Huijser and Schmid, 2011).…”

Mechanisms of epigenetic deregulation in lymphoid neoplasms

“…HDAC complexes mediate repression of miR-15a, miR-16, and miR-29b in CLL and in NHL. 104,105 Treatment with HDACi induced the expression of these miRNAs, antagonizing survival protein MCL-1 and triggering cell death. 104 Deregulated PRC2 complexes repress miR-31 in adult T-cell leukemia and lead to activation of NF-kB, triggering oncogenic signaling.…”