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http://dx.doi.org/10.4062/biomolther.2020.111

KAT8/MOF-Mediated Anti-Cancer Mechanism of Gemcitabine in Human Bladder Cancer Cells  

Zhu, Huihui (School of Life Sciences, Jilin University)
Wang, Yong (Urology Department, Jilin Province People's Hospital)
Wei, Tao (School of Life Sciences, Jilin University)
Zhao, Xiaoming (Central laboratory, China-Japan Union Hospital of Jilin University)
Li, Fuqiang (School of Pharmacy, Changchun University of Chinese Medicine)
Li, Yana (School of Life Sciences, Jilin University)
Wang, Fei (School of Life Sciences, Jilin University)
Cai, Yong (School of Life Sciences, Jilin University)
Jin, Jingji (School of Life Sciences, Jilin University)
Publication Information
Biomolecules & Therapeutics / v.29, no.2, 2021 , pp. 184-194 More about this Journal
Abstract
Histone acetylation is a well-characterized epigenetic modification controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Imbalanced histone acetylation has been observed in many primary cancers. Therefore, efforts have been made to find drugs or small molecules such as HDAC inhibitors that can revert acetylation levels to normal in cancer cells. We observed dose-dependent reduction in the endogenous and exogenous protein expression levels of KAT8 (also known as human MOF), a member of the MYST family of HATs, and its corresponding histone acetylation at H4K5, H4K8, and H4K16 in chemotherapy drug gemcitabine (GEM)-exposed T24 bladder cancer (BLCA) cells. Interestingly, the reduction in MOF and histone H4 acetylation was inversely proportional to GEM-induced γH2AX, an indicator of chemotherapy drug effectiveness. Furthermore, pGL4-MOF-Luc reporter activities were significantly inhibited by GEM, thereby suggesting that GEM utilizes an MOF-mediated anti-BLCA mechanism of action. In the CCK-8, wound healing assays and Transwell® experiments, the additive effects on cell proliferation and migration were observed in the presence of exogenous MOF and GEM. In addition, the promoted cell sensitivity to GEM by exogenous MOF in BLCA cells was confirmed using an Annexin V-FITC/PI assay. Taken together, our results provide the theoretical basis for elucidating the anti-BLCA mechanism of GEM.
Keywords
KAT8/MOF; Bladder cancer; Chemotherapy; Gemcitabine;
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1 Mendjan, S., Taipale, M., Kind, J., Holz, H., Gebhardt, P., Schelder, M., Vermeulen, M., Buscaino, A., Duncan, K., Mueller, J., Wilm, M., Stunnenberg, H. G., Saumweber, H. and Akhtar, A. (2006) Nuclear pore components are involved in the transcriptional regulation of dosage compensation in Drosophila. Mol. Cell 21, 811-823.   DOI
2 Nieder, A. M., Mackinnon, J. A., Huang, Y., Fleming, L. E., Koniaris, L. G. and Lee, D. J. (2008) Florida bladder cancer trends 1981 to 2004: minimal progress in decreasing advanced disease. J. Urol. 179, 491-495.
3 Pfister, S., Rea, S., Taipale, M., Mendrzyk, F., Straub, B., Ittrich, C., Thuerigen, O., Sinn, H. P., Akhtar, A. and Lichter, P. (2008) The histone acetyltransferase hMOF is frequently downregulated in primary breast carcinoma and medulloblastoma and constitutes a biomarker for clinical outcome in medulloblastoma. Int. J. Cancer 122, 1207-1213.   DOI
4 Rea, S., Xouri, G. and Akhtar, A. (2007) Males absent on the first (MOF): from flies to humans. Oncogene 26, 5385-5394.   DOI
5 Sanchez-Carbayo, M., Socci, N. D., Lozano, J., Saint, F. and CordonCardo, C. (2006) Defining molecular profiles of poor outcome in patients with invasive bladder cancer using oligonucleotide microarrays. J. Clin. Oncol. 24, 778-789.   DOI
6 Sharma, G. G., So, S., Gupta, A., Kumar, R., Cayrou, C., Avvakumov, N., Bhadra, U., Pandita, R. K., Porteus, M. H., Chen, D. J., Cote, J. and Pandita, T. (2010) MOF and histone H4 acetylation at lysine 16 are critical for DNA damage response and double-strand break repair. Mol. Cell. Biol. 30, 3582-3595.   DOI
7 Takeuchi, H., Mmeje, C. O., Jinesh, G. G., Taoka, R. and Kamat, A. M. (2015) Sequential gemcitabine and tamoxifen treatment enhances apoptosis and blocks transformation in bladder cancer cells. Oncol. Rep. 34, 2738-2744.   DOI
8 Shelley, M. D., Jones, G., Cleves, A., Wilt, T. J., Mason, M. D. and Kynaston, H. G. (2012) Intravesical gemcitabine therapy for non-muscle invasive bladder cancer (NMIBC): a systematic review. BJU Int. 109, 496-505.   DOI
9 Su, J., Sui, Y., Ding, J., Li, F., Shen, S., Yang, Y., Lu, Z., Wang, F., Cao, L., Liu, X., Jin, J. and Cai, Y. (2016a) Human INO80/YY1 chromatin remodeling complex transcriptionally regulates the BRCA2- and CDKN1A-interacting protein (BCCIP) in cells. Protein Cell 7, 749-760.   DOI
10 Su, J., Wang, F., Cai, Y. and Jin, J. (2016b) The functional analysis of histone acetyltransferase MOF in tumorigenesis. Int. J. Mol. Sci. 17, 99.   DOI
11 Yamazaki, D., Kurisu, S. and Takenawa, T. (2005) Regulation of cancer cell motility through actin reorganization. Cancer Sci. 96, 379-386.   DOI
12 Akhtar, A. and Becker, P. B. (2000) Activation of transcription through histone H4 acetylation by MOF, an acetyltransferase essential for dosage compensation in Drosophila. Mol. Cell 5, 367-375.   DOI
13 Biswas, S. and Rao, C. M. (2018) Epigenetic tools (The Writers, The Readers and The Erasers) and their implications in cancer therapy. Eur. J. Pharmacol. 837, 8-24.   DOI
14 Buttiglier, T. M., Tucci, M., Vignani, F., Scagliotti, G. V. and Di Maio, M. (2017) Molecular biomarkers to predict response to neoadjuvant chemotherapy for bladder cancer. Cancer Treat. Rev. 54, 1-9.   DOI
15 Wang, L. H., Pfister, T. D., Parchment, R. E., Kummar, S., Rubinstein, L., Evrard, Y. A., Gutierrez, M. E., Murgo, A. J., Tomaszewski, J. E., Doroshow, J. H. and Kinders, R. J. (2010) Monitoring drug-induced γH2AX as a pharmacodynamic biomarker in individual circulating tumor cells. Clin. Cancer Res. 16, 1073-1084.   DOI
16 Wang, Y., Zhang, R., Wu, D., Lu, Z., Sun, W., Cai, Y., Wang, C. and Jin, J. (2013) Epigenetic change in kidney tumor: downregulation of histone acetyltransferase MYST1 in human renal cell carcinoma. J. Exp. Clin. Cancer Res. 32, 8.   DOI
17 Yu, Y., Cao, H., Zhang, M., Shi, F., Wang, R. and Liu, X. (2018) Prognostic value of DNA methylation for bladder cancer. Clin. Chim. Acta 484, 207-212.   DOI
18 Zhao, L., Wang, D. L., Liu, Y., Chen, S. and Sun, F. L. (2013) Histone acetyltransferase hMOF promotes S phase entry and tumorigenesis in lung cancer. Cell. Signal. 25, 1689-1698.   DOI
19 Zhu, L., Yang, J., Zhao, L., Yu, X., Wang, L., Wang, F., Cai, Y. and Jin, J. (2015) Expression of hMOF, but not HDAC4, is responsible for the global histone H4K16 acetylation in gastric carcinoma. Int. J. Oncol. 46, 2535-2545.   DOI
20 Cai, Y., Jin, J., Swanson, S. K., Cole, M. D., Choi, S. H., Florens, L., Washburn, M. P., Conaway, J. W. and Conaway, R. C. (2010) Subunit composition and substrate specificity of a MOF-containing histone acetyltransferase distinct from the male-specific lethal (MSL) complex. J. Biol. Chem. 285, 4268-4272.   DOI
21 Cao, L., Zhu, L., Yang, J., Su, J., Ni, J., Du, Y., Liu, D., Wang, Y., Wang, F., Jin, J. and Cai, Y. (2014) Correlation of low expression of hMOF with clinicopathological features of colorectal carcinoma, gastric cancer and renal cell carcinoma. Int. J. Oncol. 44, 1207-1214.   DOI
22 Gontero, P., Casetta, G., Maso, G., Sogni, F., Pretti, G., Zitella, A., Frea, B. and Tizzani, A. (2004) Phase II study to investigate the ablative efficacy of intravesical administration of gemcitabine in intermediate-risk superficial bladder cancer (SBC). Eur. Urol. 46, 339-343.   DOI
23 Chen, Z., Ye, X., Tang, N., Shen, S., Li, Z., Niu, X., Lu, S. and Xu, L. (2014) The histone acetylranseferase hMOF acetylates Nrf2 and regulates anti-drug responses in human non-small cell lung cancer. Br. J. Pharmacol. 171, 3196-3211.   DOI
24 Cockerill, P. A., Knoedler, J. J., Frank, I., Tarrell, R. and Karnes, R. J. (2016) Intravesical gemcitabine in combination with mitomycin C as salvage treatment in recurrent non-muscle-invasive bladder cancer. BJU Int. 117, 456-462.   DOI
25 Du, C., Huang, D., Peng, Y., Yao, Y., Zhao, Y., Yang, Y., Wang, H., Cao, L., Zhu, W. G. and Gu, J. (2017) 5-Fluorouracil targets histone acetyltransferases p300/CBP in the treatment of colorectal cancer. Cancer Lett. 400, 183-193.   DOI
26 Gupta, A., Guerin-Peyrou, T. G., Sharma, G. G., Park, C., Agarwal, M., Ganju, R. K., Pandita, S., Choi, K., Sukumar, S., Pandita, R. K., Ludwig, T. and Pandita, T. K. (2008) The mammalian ortholog of Drosophila MOF that acetylates histone H4 lysine 16 is essential for embryogenesis and oncogenesis. Mol. Cell. Biol. 28, 397-409.   DOI
27 Kind, J., Vaquerizas, J. M., Gebhardt, P., Gentzel, M., Luscombe, N. M., Bertone, P. and Akhtar, A. (2008) Genome-wide analysis reveals MOF as a key regulator of dosage compensation and gene expression in Drosophila. Cell 133, 813-828.   DOI
28 Hilfiker, A., Hilfiker-Kleiner, D., Pannuti, A. and Lucchesi, J. C. (1997) mof, a putative acetyl transferase gene related to the Tip60 and MOZ human genes and to the SAS genes of yeast, is required for dosage compensation in Drosophila. EMBO J. 16, 2054-2060.   DOI
29 Jeronimo, C. and Henrique, R. (2014) Epigenetic biomarkers in urological tumors: a systematic review. Cancer Lett. 342, 264-274.   DOI
30 Kapoor-Vazirani, P., Kagey, J. D. and Vertino, M. P. (2011) SUV420H2-mediated H4K20 trimethylation enforces RNA polymerase II promoter-proximal pausing by blocking hMOF-dependent H4K16 acetylation. Mol. Cell. Biol. 31, 1594-1609.   DOI
31 Liu, D., Wu, D., Zhao, L., Yang, Y., Ding, J., Dong, L., Hu, L., Wang, F., Zhao, X., Cai, Y. and Jin, J. (2015) Arsenic trioxide reduces global histone H4 acetylation at lysine 16 through direct binding to histone acetyltransferase hMOF in human cells. PLoS ONE 10, e0141014.   DOI
32 Liu, N., Zhang, R., Zhao, X., Su, J., Bian, X., Ni, J., Yu, Y., Cai, Y. and Jin, J. (2013) A potential diagnostic marker for ovarian cancer: involvement of the histone acetyltransferase, human males absent on the first. Oncol. Lett. 6, 393-400.   DOI
33 Luo, H., Shenoy, A. K., Li, X., Jin, Y., Jin, L., Cai, Q., Tang, M., Liu, Y., Chen, H., Reisman, D., Wu, L., Seto, E., Qiu, Y., Dou, Y., Casero, R. A., Jr. and Lu, J. (2016) MOF acetylates the histone demethylase LSD1 to suppress epithelial-to-mesenchymal transition. Cell Rep. 15, 2665-2678.   DOI
34 Mellert, H. S. and McMahon, S. B. (2009) hMOF, a KAT(8) with many lives. Mol. Cell 36, 174-175.   DOI