Upregulation of AKAP12 with HDAC3 depletion suppresses the progression and migration of colorectal cancer

He,Ping; Li,Ke; Li,Shi-Bao; Hu,Ting-Ting; Guan,Ming; Sun,Fen-Yong; Liu,Wei-Wei

doi:10.3892/ijo.2018.4284

Upregulation of AKAP12 with HDAC3 depletion suppresses the progression and migration of colorectal cancer

Authors:
- Ping He
- Ke Li
- Shi-Bao Li
- Ting-Ting Hu
- Ming Guan
- Fen-Yong Sun
- Wei-Wei Liu
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Affiliations: Central Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200070, P.R. China, Department of Laboratory Medicine, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu 221100, P.R. China, Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, P.R. China, Department of Laboratory Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200070, P.R. China
Published online on: February 23, 2018 https://doi.org/10.3892/ijo.2018.4284
Pages: 1305-1316

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Abstract

A-kinase anchor protein 12 (AKAP12; also known as Gravin) functions as a tumor suppressor in several human primary cancers. However, the potential correlation between histone deacetylase 3 (HDAC3) and AKAP12 and the underlying mechanisms remain unclear. Thus, in this study, in an aim to shed light into this matter, the expression levels of HDAC3 and AKAP12 in 96 colorectal cancer (CRC) and adjacent non-cancerous tissues, as well as in SW480 cells were examined by immunohistochemical, RT-qPCR and western blot analyses. The effects of HDAC3 and AKAP12 on the proliferation, apoptosis and metastasis of CRC cells were examined by cell counting kit-8 (CCK-8) assay, colony formation assays, flow cytometry, cell cycle analysis and Transwell assays. The results revealed that the reduction or loss of AKAP12 expression was detected in 69 (71.8%) of the 96 tissue specimens, whereas HDAC3 was upregulated in 50 (52.1%) of the 96 tumor tissue specimens. AKAP12 expression was markedly increased upon treatment with the HDAC3 inhibitors, trichostatin A (TSA) and RGFP966, at both the mRNA and protein level. Mechanistically, the direct binding of HDAC3 within the intron-1 region of AKAP12 was identified to be indispensable for the inhibition of AKAP12 expression. Moreover, the proliferation, colony-forming ability, cell cycle progression and the migration of the CRC cells were found to be promoted in response to AKAP12 silencing or AKAP12/HDAC3 co-silencing, whereas transfection with si-HDAC3 yielded opposite effects. Apart from the elevated expression of the anti-apoptotic protein, Bcl-2, after AKAP12 knockdown, the increased activity of PI3K/AKT signaling was found to be indispensable for AKAP12-mediated colony formation and migration. On the whole, these findings indicate that AKAP12 may be a potential prognostic predictor and therapeutic target for the treatment of CRC in combination with HDAC3.

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