Jianhong Lin

Coordinated Silencing of MYC-Mediated miR-29 by HDAC3 and EZH2 as a Therapeutic Target of Histone Modification in Aggressive B-Cell Lymphomas

We investigated the transcriptional and epigenetic repression of miR-29 by MYC, HDAC3, and EZH2 in mantle cell lymphoma and other MYC-associated lymphomas. We demonstrate that miR-29 is repressed by MYC through a corepressor complex with HDAC3 and EZH2. MYC contributes to EZH2 upregulation via repression of the EZH2 targeting miR-26a, and EZH2 induces MYC via inhibition of the MYC targeting miR-494 to create positive feedback. Combined inhibition of HDAC3 and EZH2 cooperatively disrupted the MYC-EZH2-miR-29 axis, resulting in restoration of miR-29 expression, downregulation of miR-29-targeted genes, and lymphoma growth suppression in vitro and in vivo. These findings define a MYC-mediated miRNA repression mechanism, shed light on MYC lymphomagenesis mechanisms, and reveal promising therapeutic targets for aggressive B-cell malignancies.

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

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.

Follicular dendritic cell–dependent drug resistance of non-Hodgkin lymphoma involves cell adhesion–mediated Bim down-regulation through induction of microRNA-181a

Follicular dendritic cells (FDCs), an essential component of the lymph node microenvironment, regulate and support B-lymphocyte differentiation, survival, and lymphoma progression. Here, we demonstrate that adhesion of mantle cell lymphoma and other non-Hodgkin lymphoma cells to FDCs reduces cell apoptosis and is associated with decreased levels of the proapoptotic protein, Bim. Bim down-regulation is posttranscriptionally regulated via up-regulation of microRNA-181a (miR-181a). miR-181a overexpression decreases, whereas miR-181a inhibition increases Bim levels by directly targeting Bim. Furthermore, we found that cell adhesion-up-regulated miR-181a contributes to FDC-mediated cell survival through Bim down-regulation, implicating miR-181a as an upstream effector of the Bim-apoptosis signaling pathway. miR-181a inhibition and Bim upregulation significantly suppressed FDC-mediated protection against apoptosis in lymphoma cell lines and primary lymphoma cells. Thus, FDCs protect B-cell lymphoma cells against apoptosis, in part through activation of a miR-181a-dependent mechanism involving down-regulation of Bim expression. We demonstrate, for the first time, that cell-cell contact controls tumor cell survival and apoptosis via microRNA in mantle cell and other non-Hodgkin lymphomas. Regulation of microRNAs by B-cell-FDC interaction may support B-cell survival, representing a novel molecular mechanism for cell adhesion-mediated drug resistance and a potential therapeutic target in B-cell lymphomas.

Follicular dendritic cell-induced microRNA-mediated upregulation of PRDM1 and downregulation of BCL-6 in non-Hodgkin's B-cell lymphomas

B-cell lymphoma 6 (BCL6) and PR domain containing 1 (PRDM1) are considered as master regulators for germinal center (GC) formation and terminal B-cell differentiation. Dysregulation of BCL6 and PRDM1 has been associated with lymphomagenesis. Here, we show for the first time that direct cell–cell contact between follicular dendritic cells (FDC) and B-lymphocytes, by influencing the expression of a set of microRNAs (miRNAs), regulates the expression of BCL6 and PRDM1. We identify that, on cell adhesion to FDC, FDC induces upregulation of PRDM1 expression through downregulation of miR-9 and let-7 families and induces downregulation of BCL-6 through upregulation of miR-30 family in B-lymphocytes and lymphoma cells. We further demonstrate that the miR-30 family directly controls BCL-6 expression and miR-9-1 and let-7a directly control PRDM-1 expression through targeting their 3′UTR, mediating the FDC effect. Our studies define a novel regulatory mechanism in which the FDC, through induction of miRNAs in B-lymphocytes, orchestrates the regulation of transcription factors, promotes germinal center B-cell survival and differentiation. Dysregulation of miRNAs may interfere with B-cell survival and maturation, thus representing a novel molecular mechanism, as well as a potential therapeutic target in B-cell lymphomas.