Myc-Mediated Transcriptional Repression by Recruitment of Histone Deacetylase

Kurland, John F.; Tansey, William P.

doi:10.1158/0008-5472.can-07-6552

Cited by 94 publications

(88 citation statements)

References 22 publications

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“…18 MYC can repress protein-coding genes and miRNA by recruiting HDACs, including HDAC3. 5,19 Previously, MYC was reported to repress the miR-15 and let-7 families in B-cell lymphoma, as it was enriched at the promoter regions of these miRNA. 12 Our results, in combination with genome-wide MYC ChIP-sequencing data, 17 indicate that MYC was also present at the promoter regions of the miR-15 and let-7 families in human breast and lung cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibition reveals a tumor-suppressive function of MYC-regulated miRNA in breast and lung carcinoma

Adams

Eischen

2016

Cell Death Differ

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Histone deacetylase (HDAC) inhibition leads to dynamic changes in the epigenetic landscape that is postulated to alter the expression of critical mediators of cellular proliferation and death. While current HDAC inhibitors have shown to be efficacious in the treatment of specific hematologic malignancies, their therapeutic utility in epithelial-based cancers warrants further evaluation. Moreover, the mechanisms of HDAC inhibition-induced cancer cell death are not completely understood. Therefore, elucidation of the underlying pathways engaged by HDAC inhibition may enable the development of more effective therapeutic strategies. Here, we report that HDAC inhibition in human breast and lung carcinoma cells activates an apoptotic mechanism mediated by microRNA (miRNA) and induced by the oncogene MYC. Specifically, following HDAC inhibition, MYC, which normally represses miR-15 and let-7 families, transcriptionally activated their expression and MYC was required for this miRNA upregulation. As a result, transcript levels of the tumor-suppressive miR-15 and let-7 families increased, which targeted and decreased the expression of the crucial prosurvival genes BCL-2 and BCL-X L , respectively. MYC was also required for the downregulation of BCL-2 and BCL-X L following HDAC inhibition. Blocking the binding sites of the miR-15 and let-7 families in the 3′-untranslated regions of BCL-2 and BCL-X L protected against HDAC inhibition-induced apoptosis. These results provide important insight into the molecular underpinnings of HDAC inhibition-induced cell death in breast and lung cancer and reveal a tumor-suppressive role for MYCregulated miRNA that is activated with HDAC inhibition.

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Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibition reveals a tumor-suppressive function of MYC-regulated miRNA in breast and lung carcinoma

Adams

Eischen

2016

Cell Death Differ

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“…As multiple biochemical studies have shown that the two directly interact with each other, we sought to look for the de-repressed targets that may require both BCL6 and HDAC4 in the up-regulated dataset from Eμ-miR-155 mice. Interestingly, one of the key BCL6 target genes, Id2, up-regulation of which inhibits B-cell differentiation, has been proposed to require HDAC4 as one of the repressors (33). Therefore, we propose that BCL6 may recruit HDAC4 to the promoter of Id2 to suppress its transcription.…”

Section: Bcl6 Transcription Is Indirectly Modulated By Mir-155 Througmentioning

confidence: 90%

miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eµ-miR-155 transgenic mouse model

Sandhu

Volinia

Costinean

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

121

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Multiple studies have established that microRNAs (miRNAs) are involved in the initiation and progression of cancer. Notably, miR-155 is one of the most overexpressed miRNAs in several solid and hematological malignancies. Ectopic miR-155 expression in mice B cells (Eμ-miR-155 transgenic mice) has been shown to induce pre-B-cell proliferation followed by high-grade lymphoma/leukemia. Loss of miR-155 in mice resulted in impaired immunity due to defective T-cell-mediated immune response. Here we provide a mechanistic insight into miR-155-induced leukemogenesis in the Eμ-miR-155 mouse model through genome-wide transcriptome analysis of naïve B cells and target studies. We found that a key transcriptional repressor and proto-oncogene, Bcl6 is significantly down-regulated in Eμ-miR-155 mice. The reduction of Bcl6 subsequently leads to de-repression of some of the known Bcl6 targets like inhibitor of differentiation (Id2), interleukin-6 (IL6), cMyc, Cyclin D1, and Mip1α/ccl3, all of which promote cell survival and proliferation. We show that Bcl6 is indirectly regulated by miR-155 through Mxd1/Mad1 up-regulation. Interestingly, we found that miR-155 directly targets HDAC4, a corepressor partner of BCL6. Furthermore, ectopic expression of HDAC4 in human-activated B-cell-type diffuse large B-cell lymphoma (DLBCL) cells results in reduced miR-155-induced proliferation, clonogenic potential, and increased apoptosis. Meta-analysis of the diffuse large B-cell lymphoma patient microarray data showed that miR-155 expression is inversely correlated with Bcl6 and Hdac4. Hence this study provides a better understanding of how miR-155 causes disruption of the BCL6 transcriptional machinery that leads to up-regulation of the survival and proliferation genes in miR-155-induced leukemias.NfκB | Ingenuity Pathway Analysis M icroRNAs (miRNAs) are 18-24-nucleotide-long noncoding RNA molecules that regulate gene expression in many cellular processes including proliferation, differentiation, and development. Recent studies have established that expression of miRNAs is widely altered in a variety of cancers and miR-155 is one of the most frequently overexpressed miRNAs in various solid and hematological malignancies (1). miR-155 is highly upregulated in Hodgkin, primary mediastinal, and diffuse large B-cell lymphomas (DLBCL) (2, 3) and is almost absent or significantly down-regulated in primary cases of Burkitt lymphoma (4). Overexpression of bic, host mRNA of miR-155, caused increased incidence of leukemia and a decrease in latency of lymphoma development in chickens with elevated levels of MYC (5). Overexpression of miR-155 in mice B cells (Eμ-miR-155) has been shown to cause pre-B-cell leukemia/high-grade lymphoma (6), whereas deletion of bic/miR-155 in mice has been attributed to immunodeficiency and impaired T-cell-dependent antibody response (7,8). Additionally, sustained miR-155 expression in stem cell progenitors induced a myeloproliferative disease in transplanted mice (9). Despite the availability of multiple animal models and a ...

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“…HDACs also facilitate MYC's oncogenic function as a transcription factor, as they are often recruited to the promoter regions of some MYC-targeted genes to facilitate MYC-mediated regulation of transcription. HDAC inhibitors thus decrease MYC gene expression and restore the expression of genes coordinately suppressed by MYC family members and HDACs in multiple cancer cell types, including DLBCL and NMC (19)(20)(21)(22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers

Sun

Atoyan

Borek

et al. 2017

Molecular Cancer Therapeutics

117

100

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Upregulation of MYC is a common driver event in human cancers, and some tumors depend on MYC to maintain transcriptional programs that promote cell growth and proliferation. Preclinical studies have suggested that individually targeting upstream regulators of MYC, such as histone deacetylases (HDAC) and phosphoinositide 3-kinases (PI3K), can reduce MYC protein levels and suppress the growth of MYCdriven cancers. Synergy between HDAC and PI3K inhibition in inducing cancer cell death has also been reported, but the involvement of MYC regulation is unclear. In this study, we demonstrated that HDAC and PI3K inhibition synergistically downregulates MYC protein levels and induces apoptosis in "double-hit" (DH) diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, CUDC-907, a small-molecule dual-acting inhibitor of both class I and II HDACs and class I PI3Ks, effectively suppresses the growth and survival of MYC-altered or MYC-dependent cancer cells, such as DH DLBCL and BRD-NUT fusion-positive NUT midline carcinoma (NMC) cells, and MYC protein downregulation is an early event induced by CUDC-907 treatment. Consistently, the antitumor activity of CUDC-907 against multiple MYC-driven cancer types was also demonstrated in animal models, including DLBCL and NMC xenograft models, Myc transgenic tumor syngeneic models, and MYC-amplified solid tumor patient-derived xenograft (PDX) models. Our findings suggest that dual function HDAC and PI3K inhibitor CUDC-907 is an effective agent targeting MYC and thus may be developed as potential therapy for MYCdependent cancers.

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Myc-Mediated Transcriptional Repression by Recruitment of Histone Deacetylase

Cited by 94 publications

References 22 publications

Histone deacetylase inhibition reveals a tumor-suppressive function of MYC-regulated miRNA in breast and lung carcinoma

Histone deacetylase inhibition reveals a tumor-suppressive function of MYC-regulated miRNA in breast and lung carcinoma

miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eµ-miR-155 transgenic mouse model

Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers

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