CHI-KAT8i5 suppresses ESCC tumor growth by inhibiting KAT8-mediated c-Myc stability
Dandan Zhang,
Ming Jiang,
Pan Li,
Kyle Vaughn Laster,
Dengyun Zhao,
Yafei Zhi,
Huifang Wei,
Wenna Nie,
Yunfeng Gao,
Qiong Wu,
Pu Xiang,
Xinyu He,
Kangdong Liu,
Zigang Dong
Affiliations
Dandan Zhang
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000 Henan, China; China-US (Henan) Hormel Cancer Institute, No. 127, Zhengzhou 450000 Henan, China
Ming Jiang
China-US (Henan) Hormel Cancer Institute, No. 127, Zhengzhou 450000 Henan, China
Pan Li
China-US (Henan) Hormel Cancer Institute, No. 127, Zhengzhou 450000 Henan, China
Kyle Vaughn Laster
China-US (Henan) Hormel Cancer Institute, No. 127, Zhengzhou 450000 Henan, China
Dengyun Zhao
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000 Henan, China; China-US (Henan) Hormel Cancer Institute, No. 127, Zhengzhou 450000 Henan, China
Yafei Zhi
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000 Henan, China; China-US (Henan) Hormel Cancer Institute, No. 127, Zhengzhou 450000 Henan, China
Huifang Wei
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000 Henan, China; China-US (Henan) Hormel Cancer Institute, No. 127, Zhengzhou 450000 Henan, China
Wenna Nie
China-US (Henan) Hormel Cancer Institute, No. 127, Zhengzhou 450000 Henan, China
Yunfeng Gao
China-US (Henan) Hormel Cancer Institute, No. 127, Zhengzhou 450000 Henan, China
Qiong Wu
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000 Henan, China; China-US (Henan) Hormel Cancer Institute, No. 127, Zhengzhou 450000 Henan, China
Pu Xiang
Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450000 Henan, China
Xinyu He
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000 Henan, China; China-US (Henan) Hormel Cancer Institute, No. 127, Zhengzhou 450000 Henan, China
Kangdong Liu
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000 Henan, China; China-US (Henan) Hormel Cancer Institute, No. 127, Zhengzhou 450000 Henan, China; The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou 450000 Henan, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450000 Henan, China; Corresponding author
Zigang Dong
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000 Henan, China; China-US (Henan) Hormel Cancer Institute, No. 127, Zhengzhou 450000 Henan, China; The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou 450000 Henan, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450000 Henan, China; Corresponding author
Summary: The integrated analysis of histone modifier enzymes in solid tumors, especially in esophageal squamous cell carcinoma (ESCC), is still inadequate. Here, we investigate the expression levels of histone modifier enzymes in ESCC tissues. Notably, KAT8 (lysine acetyltransferase 8) is identified as a prognostic and therapeutic biomarker in ESCC. Esophageal-tissue-specific deletion of KAT8 in mice led to less tumor burden after induction of tumorigenesis via 4-nitroquinoline N-oxide (4NQO) treatment compared with wild-type mice. Meanwhile, silencing KAT8 significantly suppresses tumor growth in cell-line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Mechanically, we confirm that KAT8 regulates c-Myc protein stability by directly binding it. Furthermore, we design and screen a specific KAT8 inhibitor (CHI-KAT8i5) that significantly attenuates tumor growth in vitro and in vivo, providing promising potential for clinical application. Thus, our work identifies that KAT8 could serve as a potential clinically relevant biomarker and therapeutic target in patients with ESCC and that KAT8 inhibitor is a promising lead candidate for ESCC therapy.
