2. Academic Validation
  3. The hydroxamate based HDAC inhibitor WMJ-J-09 induces colorectal cancer cell death by targeting tubulin and downregulating survivin

The hydroxamate based HDAC inhibitor WMJ-J-09 induces colorectal cancer cell death by targeting tubulin and downregulating survivin

  • Sci Rep. 2025 Jun 4;15(1):19590. doi: 10.1038/s41598-025-04714-w.
Yu-Han Huang # 1,  Yu-Min Huang # 2 3,  Wei-Jan Huang 4,  Meng-Chieh Yu 5,  Chin-Hui Chuang 5 6,  Ya-Fen Hsu 7,  Hsiu-Chen Chen 5,  Liang-Chieh Chen 8,  Shiu-Wen Huang 9 10 11,  Ming-Jen Hsu 12 13 14 15
Affiliations

Affiliations

  • 1 Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
  • 2 Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 3 Division of Gastrointestinal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.
  • 4 Department of Pharmaceutical Sciences, Taipei Medical University, Taipei, Taiwan.
  • 5 Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 6 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 7 Division of General Surgery, Department of Surgery, Landseed Hospital, Taoyuan, Taiwan.
  • 8 School of Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan.
  • 9 Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. shiuwen@tmu.edu.tw.
  • 10 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. shiuwen@tmu.edu.tw.
  • 11 Research Center of Thoracic Medicine, Taipei Medical University Hospital, Taipei, Taiwan. shiuwen@tmu.edu.tw.
  • 12 Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. aspirin@tmu.edu.tw.
  • 13 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. aspirin@tmu.edu.tw.
  • 14 Research Center of Thoracic Medicine, Taipei Medical University Hospital, Taipei, Taiwan. aspirin@tmu.edu.tw.
  • 15 Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. aspirin@tmu.edu.tw.
  • # Contributed equally.
PMID: 40467895 DOI: 10.1038/s41598-025-04714-w
Abstract

Aberrant expression of histone deacetylases (HDACs) is associated with Cancer Drug Resistance and tumor progression. While considerable studies and effort have been devoted to developing novel HDAC inhibitors in Cancer therapy, hydroxamate-based HDAC inhibitors have gained growing interest for their broad-spectrum anti-tumor properties. We developed a series of HDAC inhibitors featuring a hydroxamate moiety, and WMJ-J-09 was selected due to its potent cytotoxic effect in colorectal Cancer (CRC) cells, and its molecular mechanisms driving CRC cell death were characterized. WMJ-J-09 reduced cell viability, arrested the cell cycle at the G2/M phase, and triggered Apoptosis. Mechanistically, it activated LKB1-p38MAPK signaling, leading to p53 phosphorylation and acetylation, which elevated p21 and suppressed Survivin levels. WMJ-J-09 also acetylated α-tubulin, impaired microtubule assembly, and acetylated Survivin, resulting in proteasomal degradation. Both LKB1 siRNA and anacardic acid, a Histone Acetyltransferase Inhibitor, reversed WMJ-J-09-reduced Survivin, confirming its dual effects on Survivin at transcriptional and post-translational levels. In vivo, the subcutaneous growth of HCT116 CRC xenografts was reduced by WMJ-J-09. In conclusion, WMJ-J-09 causes CRC cell death via the LKB1-p53-survivin signaling pathway and HDAC inhibition, leading to acetylation of α-tubulin, p53, and Survivin. This study highlights WMJ-J-09's potential as a promising therapeutic candidate for CRC treatment.

Keywords

Acetylation; Histone deacetylase (HDAC); Liver kinase B1 (LKB1); P53; Survivin.

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