2. Academic Validation
  3. Targeting the E2F1/Rb/HDAC1 axis with the small molecule HR488B effectively inhibits colorectal cancer growth

Targeting the E2F1/Rb/HDAC1 axis with the small molecule HR488B effectively inhibits colorectal cancer growth

  • Cell Death Dis. 2023 Dec 7;14(12):801. doi: 10.1038/s41419-023-06205-0.
Namin Duan # 1,  Xiaohui Hu # 1,  Huiran Qiu # 2,  Rui Zhou 1,  Yuru Li 1,  Wenxia Lu 2,  Yamin Zhu 1 3 4,  Shuang Shen 5,  Wenhui Wu 3 4 6,  Feifei Yang 7,  Ning Liu 8 9 10 11 12
Affiliations

Affiliations

  • 1 Department of Chemistry, College of Food Science and Technology, Shanghai Ocean University, Shanghai, China.
  • 2 School of Biological Science and Technology, University of Jinan, Jinan, P.R. China.
  • 3 Marine Biomedical Science and Technology Innovation Platform of Lingang Special Area, Shanghai, China.
  • 4 National Experimental Teaching Demonstration Center for Food Science and Engineering, Shanghai Ocean University, Shanghai, China.
  • 5 Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
  • 6 Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai, China.
  • 7 School of Biological Science and Technology, University of Jinan, Jinan, P.R. China. bio_yangff@ujn.edu.cn.
  • 8 Department of Chemistry, College of Food Science and Technology, Shanghai Ocean University, Shanghai, China. nliu@shou.edu.cn.
  • 9 Marine Biomedical Science and Technology Innovation Platform of Lingang Special Area, Shanghai, China. nliu@shou.edu.cn.
  • 10 National Experimental Teaching Demonstration Center for Food Science and Engineering, Shanghai Ocean University, Shanghai, China. nliu@shou.edu.cn.
  • 11 Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai, China. nliu@shou.edu.cn.
  • 12 Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA. nliu@shou.edu.cn.
  • # Contributed equally.
PMID: 38062013 DOI: 10.1038/s41419-023-06205-0
Abstract

Colorectal Cancer (CRC), the third most common Cancer worldwide, remains highly lethal as the disease only becomes symptomatic at an advanced stage. Growing evidence suggests that histone deacetylases (HDACs), a group of epigenetic Enzymes overexpressed in precancerous lesions of CRC, may represent promising molecular targets for CRC treatment. Histone deacetylase inhibitors (HDACis) have gradually become powerful anti-cancer agents targeting epigenetic modulation and have been widely used in the clinical treatment of hematologic malignancies, while only few studies on the benefit of HDACis in the treatment of CRC. In the present study, we designed a series of small-molecule Thiazole-based HDACis, among which HR488B bound to HDAC1 with a high affinity and exerted effective anti-CRC activity both in vitro and in vivo. Moreover, we revealed that HR488B specifically suppressed the growth of CRC cells by inducing cell cycle G0/G1 arrest and Apoptosis via causing mitochondrial dysfunction, Reactive Oxygen Species (ROS) generation, and DNA damage accumulation. Importantly, we noticed that HR488B significantly decreased the expression of the E2F transcription factor 1 (E2F1), which was crucial for the inhibitory effect of HR488B on CRC. Mechanistically, HR488B obviously decreased the phosphorylation level of the retinoblastoma protein (Rb), and subsequently prevented the release of E2F1 from the E2F1/Rb/HDAC1 complex, which ultimately suppressed the growth of CRC cells. Overall, our study suggests that HR488B, a novel and efficient HDAC1 Inhibitor, may be a potential candidate for CRC therapy in the future. Furthermore, targeting the E2F1/Rb/HDAC1 axis with HR488B provides a promising therapeutic avenue for CRC.

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