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Lymphoma

HDAC6 regulates microRNA-27b that suppresses proliferation, promotes apoptosis and target MET in diffuse large B-cell lymphoma

Leukemia volume 32, pages 703–711 (2018)Cite this article

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Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Histone deacetylase 6 (HDAC6) is frequently altered in DLBCL and inhibition of HDAC6 has potent anti-tumor effects in vitro and in vivo. We profiled miRNAs that altered in the HDAC6 knockdown DLBCL cells with NanoString nCounter assay and identified microRNA-27b (miR-27b) as the most significantly increased miRNA. We validated decreased expression of miR-27b in DLBCL tissues, and we found that low expression of miR-27b was associated with poor overall survival of patients with DLBCL. In addition, forced expression of miR-27b suppressed DLBCL cell viability and proliferation in vitro, and inhibited tumor growth in vivo. Mechanistically, Rel A/p65 is found to negatively regulate miR-27b expression, and its acetylation and block of nuclear translocalization caused by HDAC6 inhibition significantly elevates miR-27b expression. Furthermore, miR-27b targets MET and thus represses the MET/PI3K/AKT pathway. These findings highlight an important role of miR-27b in the development of DLBCL and uncover a HDAC6-Rel A/p65-miR-27b-MET signaling pathway. Elevating miR-27b through HDAC6 inhibition would be a promising strategy for DLBCL treatment.

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Acknowledgements

The work was supported by the National Natural Science Foundation of China (No. 81470353, 81272630, XYZ), Science and Technology commission of Shanghai Municipality (15495810300), Shanghai hospital development center Emerging advanced technology joint research project (SHDC 12014105) and Shanghai Municipal Commission of Health and Family Planning (2015ZB0204). This work was also supported by the Sister Institution Network Funds of UT MD Anderson Cancer Center to MJY, and matching fund from Shanghai Cancer Center to XYZ. MJY was partially supported by NIH/NCI R01 CA164346, and R01 CA200703, Developmental Research Awards in Leukemia SPORE CA100632 and CPRIT RP140402. We would like to thank Dr Emilia L Lim and Dr Marco A Marra at University of British Columbia for kindly providing their original data.

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  1. Y J Jia and Z B Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China

    Y J Jia, Z B Liu, W G Wang, C B Sun, P Wei, B H Yu, X Q Li & X Y Zhou

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    Y J Jia, Z B Liu, W G Wang, C B Sun, P Wei, B H Yu, X Q Li & X Y Zhou

  3. Institute of Pathology, Fudan University, Shanghai, China

    Y J Jia, Z B Liu, W G Wang, C B Sun, P Wei, B H Yu, X Q Li & X Y Zhou

  4. Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

    Z B Liu

  5. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Y L Yang & M J You

  6. The University of Texas MD Anderson Cancer Center, UT Health Graduate School of Biomedical Sciences, Houston, TX, USA

    M J You

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Jia, Y., Liu, Z., Wang, W. et al. HDAC6 regulates microRNA-27b that suppresses proliferation, promotes apoptosis and target MET in diffuse large B-cell lymphoma. Leukemia 32, 703–711 (2018). https://doi.org/10.1038/leu.2017.299

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