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MicroRNA-29c functions as a tumor suppressor by direct targeting oncogenic SIRT1 in hepatocellular carcinoma

Oncogene volume 33, pages 2557–2567 (2014)Cite this article

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Abstract

Mammalian sirtuin 1 (SIRT1) has connected to an ever widening circle of activities that encompass cellular stress resistance, energy metabolism and tumorigenesis. However, underlying mechanisms leading to oncogenic SIRT1 overexpression are less understood. In this study, we identified SIRT1 regulatory microRNA (miRNA) and its function in hepatocellular carcinoma (HCC). Aberrant SIRT1 overexpression was demonstrated in a subset of human HCCs. SIRT1 knockdown suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins. This led to hypophosphorylation of pRb, which inactivated E2F/DP1 target gene transcription, and thereby caused significant increase of HCC cells to remain in the G1/S phase. A comprehensive miRNA profiling analysis indentified five putative endogenous miRNAs that are significantly downregulated in HCC. Ectopic expression of miRNA mimics evidenced miR-29c to suppress SIRT1 in HCC cells. Notably, ectopic miR-29c expression repressed cancer cell growth and proliferation, and it recapitulated SIRT1 knockdown effects in HCC cells. In addition, miR-29c expression was downregulated in a large cohort of HCC patients, and low expression of miR-29c was significantly associated with poor prognosis of HCC patients. Taken together, we demonstrated that miR-29c suppresses oncogenic SIRT1 by way of binding to 3′-untranslated region of SIRT1 mRNA causing translational inhibition in liver cancer cells. The loss or suppression of miR-29c may cause aberrant SIRT1 overexpression and promotes liver tumorigenesis. Overall, we suggest that miR-29c functions as a tumor suppressor by regulating abnormal SIRT1 activity in liver.

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (MEST; Grant No. 2011-0010705 and No. 2012M3A9D1054476), and by the Korean Science and Engineering Foundation via the ‘Cancer Evolution Research Center’ at the Catholic University of Korea.

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Authors and Affiliations

  1. Department of Pathology, Laboratory of Oncogenomics, College of Medicine, Catholic University of Korea, Seoul, Republic of Korea

    H J Bae, J H Noh, J K Kim, J W Eun, K H Jung, M G Kim, Y G Chang, Q Shen, S-J Kim, W S Park, J Y Lee & S W Nam

  2. Functional RNomics Research Center, Catholic University of Korea, Seoul, Republic of Korea

    H J Bae, J H Noh, J K Kim, J W Eun, K H Jung, M G Kim, Y G Chang, Q Shen, S-J Kim, W S Park, J Y Lee & S W Nam

  3. Cancer Evolution Research Center, Catholic University of Korea, Seoul, Republic of Korea

    S W Nam

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  1. H J Bae
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Bae, H., Noh, J., Kim, J. et al. MicroRNA-29c functions as a tumor suppressor by direct targeting oncogenic SIRT1 in hepatocellular carcinoma. Oncogene 33, 2557–2567 (2014). https://doi.org/10.1038/onc.2013.216

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