Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2020.111
KAT8/MOF-Mediated Anti-Cancer Mechanism of Gemcitabine in Human Bladder Cancer Cells
Huihui Zhu1, Yong Wang2, Tao Wei1, Xiaoming Zhao3, Fuqiang Li4, Yana Li1,5, Fei Wang1, Yong Cai1,4,* and Jingji Jin1,4,*
1School of Life Sciences, Jilin University, Jilin 130012,
2Urology Department, Jilin Province People’s Hospital, Jilin 130021,
3Central laboratory, China-Japan Union Hospital of Jilin University, Jilin 130031,
4School of Pharmacy, Changchun University of Chinese Medicine, Jilin 130117,
5Department of Ophthalmology and Otorhinolaryngology, Changchun Children’s Hospital, Jilin 130061, China
*E-mail: caiyong62@jlu.edu.cn (Cai Y), jjjin@jlu.edu.cn (Jin J)
Tel: +86-431-8515-5475 (Cai Y), +86-431-8515-5475 (Jin J)
Fax: +86-431-8515-5132 (Cai Y), +86-431-8515-5132 (Jin J)
Received: June 28, 2020; Revised: July 29, 2020; Accepted: August 25, 2020; Published online: October 12, 2020.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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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