2. Academic Validation
  3. The histone acetyltransferase HBO1 functions as a novel oncogenic gene in osteosarcoma

The histone acetyltransferase HBO1 functions as a novel oncogenic gene in osteosarcoma

  • Theranostics. 2021 Mar 4;11(10):4599-4615. doi: 10.7150/thno.55655.
Yan-Yang Gao 1,  Zhuo-Yan Ling 2,  Yun-Rong Zhu 3,  Ce Shi 4,  Yin Wang 5,  Xiang-Yang Zhang 2,  Zhi-Qing Zhang 5,  Qin Jiang 6,  Min-Bin Chen 7,  Shuofei Yang 8,  Cong Cao 5 9
Affiliations

Affiliations

  • 1 Department of Pediatrics, Xinyi people's Hospital, Xinyi, China.
  • 2 Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou, China.
  • 3 Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical College of Southeast University, Jiangyin, China.
  • 4 Department of Orthopedics, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, China.
  • 5 Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.
  • 6 The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
  • 7 Department of Radiotherapy and Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China.
  • 8 Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
  • 9 North District, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China.
PMID: 33754016 DOI: 10.7150/thno.55655
Abstract

HBO1 (KAT7 or MYST2) is a Histone Acetyltransferase that acetylates H3 and H4 histones. Methods: HBO1 expression was tested in human OS tissues and cells. Genetic strategies, including shRNA, CRISPR/Cas9 and overexpression constructs, were applied to exogenously alter HBO1 expression in OS cells. The HBO1 Inhibitor WM-3835 was utilized to block HBO1 activation. Results:HBO1 mRNA and protein expression is significantly elevated in OS tissues and cells. In established (MG63/U2OS lines) and primary human OS cells, shRNA-mediated HBO1 silencing and CRISPR/Cas9-induced HBO1 knockout were able to potently inhibit cell viability, growth, proliferation, as well as cell migration and invasion. Significant increase of Apoptosis was detected in HBO1-silenced/knockout OS cells. Conversely, ectopic HBO1 overexpression promoted OS cell proliferation and migration. We identified ZNF384 (zinc finger protein 384) as a potential transcription factor of HBO1. Increased binding between ZNF384 and HBO1 promoter was detected in OS cell and tissues, whereas ZNF384 silencing via shRNA downregulated HBO1 and produced significant anti-OS cell activity. In vivo, intratumoral injection of HBO1 shRNA lentivirus silenced HBO1 and inhibited OS xenograft growth in mice. Furthermore, growth of HBO1-knockout OS xenografts was significantly slower than the control xenografts. WM-3835, a novel and high-specific small molecule HBO1 Inhibitor, was able to potently suppressed OS cell proliferation and migration, and led to Apoptosis activation. Furthermore, intraperitoneal injection of a single dose of WM-3835 potently inhibited OS xenograft growth in SCID mice. Conclusion: HBO1 overexpression promotes OS cell growth in vitro and in vivo.

Keywords

HBO1; WM-3835; histone acetylation; osteosarcoma.

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