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Theranostics 2021; 11(13):6278-6292. doi:10.7150/thno.57455 This issue Cite

Research Paper

KAT6A, a novel regulator of β-catenin, promotes tumorigenicity and chemoresistance in ovarian cancer by acetylating COP1

Wenxue Liu^1*, Zhiyan Zhan^2,3*, Meiying Zhang^4*, Bowen Sun¹, Qiqi Shi¹, Fei Luo¹, Mingda Zhang¹, Weiwei Zhang¹, Yanli Hou⁵, Xiuying Xiao^6✉, Yanxin Li^2✉, Haizhong Feng^1✉

1. State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
2. Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Department of Hematology & Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
3. Department of Clinical Nutrition, Shanghai Children's Medical Center, School of Medicine Shanghai Jiao Tong University, Shanghai, 200127, China.
4. Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
5. Department of Radiotherapy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
6. Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
*These authors contributed equally to this work.

✉ Corresponding authors: Haizhong Feng, E-mail: fenghaizhongedu.cn, Phone: 86-21-68383921; Fax: 86-21-68383916, Yanxin Li, E-mail: liyanxincom.cn, or Xiuying Xiao, E-mail: xiaoxiuying2002com.

Abstract

Background: Ovarian cancer is a fatal gynecologic malignancy that is found worldwide and exhibits an insidious onset and a lack of early warning symptoms. Despite ongoing studies, the mechanistic basis of the aggressive phenotypes of ovarian cancer remains unclear. Lysine acetyltransferase 6A (KAT6A) is a MYST-type histone acetyltransferase (HAT) enzyme identified as an oncogene in breast cancer, glioblastoma and leukemia. However, the specific functions of KAT6A in ovarian cancer remain unclear.

Methods: Immunohistochemistry (IHC) staining and western blotting were performed to characterize KAT6A protein expression in ovarian cancer tissues and cell lines. The biological functions of KAT6A in ovarian cancer were evaluated by cell proliferation, wound healing and transwell invasion assays in vitro. Tumorigenesis and metastasis assays were performed in nude mice to detect the role of KAT6A in vivo. Mass spectrometry and immunoprecipitation assays were performed to detect the KAT6A-COP1 interaction. An in vivo ubiquitination assay was performed to determine the regulation of β-catenin by KAT6A.

Results: In the present study, we revealed that KAT6A expression is upregulated in ovarian cancer and is associated with patient overall survival. Downregulation of KAT6A markedly inhibited the proliferation and migration abilities of ovarian cancer cells in vivo and in vitro. Additionally, the inhibition of KAT6A induced apoptosis and enhanced the sensitivity of ovarian cancer cells to cisplatin. Furthermore, KAT6A bound to and acetylated COP1 at K294. The acetylation of COP1 impaired COP1 function as an E3 ubiquitin ligase and led to the accumulation and enhanced activity of β-catenin.

Conclusions: Our findings suggest that the KAT6A/COP1/β-catenin signaling axis plays a critical role in ovarian cancer progression and that targeting the KAT6A/COP1/β-catenin signaling axis could be a novel strategy for treating ovarian cancer.

Keywords: KAT6A, ovarian cancer, acetylation, COP1, β-catenin

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