The hydroxamate based HDAC inhibitor WMJ-J-09 induces colorectal cancer cell death by targeting tubulin and downregulating survivin
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...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-06-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-025-04714-w |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849434349725810688 |
|---|---|
| author | Yu-Han Huang Yu-Min Huang Wei-Jan Huang Meng-Chieh Yu Chin-Hui Chuang Ya-Fen Hsu Hsiu-Chen Chen Liang-Chieh Chen Shiu-Wen Huang Ming-Jen Hsu |
| author_facet | Yu-Han Huang Yu-Min Huang Wei-Jan Huang Meng-Chieh Yu Chin-Hui Chuang Ya-Fen Hsu Hsiu-Chen Chen Liang-Chieh Chen Shiu-Wen Huang Ming-Jen Hsu |
| author_sort | Yu-Han Huang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-aa9a13c681244825bcfce7e5bb343041 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-aa9a13c681244825bcfce7e5bb3430412025-08-20T03:26:42ZengNature PortfolioScientific Reports2045-23222025-06-0115111710.1038/s41598-025-04714-wThe hydroxamate based HDAC inhibitor WMJ-J-09 induces colorectal cancer cell death by targeting tubulin and downregulating survivinYu-Han Huang0Yu-Min Huang1Wei-Jan Huang2Meng-Chieh Yu3Chin-Hui Chuang4Ya-Fen Hsu5Hsiu-Chen Chen6Liang-Chieh Chen7Shiu-Wen Huang8Ming-Jen Hsu9Division of Genetics and Genomics, Department of Pediatrics, Boston Children’s HospitalDepartment of Surgery, School of Medicine, College of Medicine, Taipei Medical UniversityDepartment of Pharmaceutical Sciences, Taipei Medical UniversityDepartment of Pharmacology, School of Medicine, College of Medicine, Taipei Medical UniversityDepartment of Pharmacology, School of Medicine, College of Medicine, Taipei Medical UniversityDivision of General Surgery, Department of Surgery, Landseed HospitalDepartment of Pharmacology, School of Medicine, College of Medicine, Taipei Medical UniversitySchool of Medicine, National Sun Yat-Sen UniversityDepartment of Pharmacology, School of Medicine, College of Medicine, Taipei Medical UniversityDepartment of Pharmacology, School of Medicine, College of Medicine, Taipei Medical UniversityAbstract 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.https://doi.org/10.1038/s41598-025-04714-wAcetylationHistone deacetylase (HDAC)Liver kinase B1 (LKB1)P53Survivin |
| spellingShingle | Yu-Han Huang Yu-Min Huang Wei-Jan Huang Meng-Chieh Yu Chin-Hui Chuang Ya-Fen Hsu Hsiu-Chen Chen Liang-Chieh Chen Shiu-Wen Huang Ming-Jen Hsu The hydroxamate based HDAC inhibitor WMJ-J-09 induces colorectal cancer cell death by targeting tubulin and downregulating survivin Scientific Reports Acetylation Histone deacetylase (HDAC) Liver kinase B1 (LKB1) P53 Survivin |
| title | The hydroxamate based HDAC inhibitor WMJ-J-09 induces colorectal cancer cell death by targeting tubulin and downregulating survivin |
| title_full | The hydroxamate based HDAC inhibitor WMJ-J-09 induces colorectal cancer cell death by targeting tubulin and downregulating survivin |
| title_fullStr | The hydroxamate based HDAC inhibitor WMJ-J-09 induces colorectal cancer cell death by targeting tubulin and downregulating survivin |
| title_full_unstemmed | The hydroxamate based HDAC inhibitor WMJ-J-09 induces colorectal cancer cell death by targeting tubulin and downregulating survivin |
| title_short | The hydroxamate based HDAC inhibitor WMJ-J-09 induces colorectal cancer cell death by targeting tubulin and downregulating survivin |
| title_sort | hydroxamate based hdac inhibitor wmj j 09 induces colorectal cancer cell death by targeting tubulin and downregulating survivin |
| topic | Acetylation Histone deacetylase (HDAC) Liver kinase B1 (LKB1) P53 Survivin |
| url | https://doi.org/10.1038/s41598-025-04714-w |
| work_keys_str_mv | AT yuhanhuang thehydroxamatebasedhdacinhibitorwmjj09inducescolorectalcancercelldeathbytargetingtubulinanddownregulatingsurvivin AT yuminhuang thehydroxamatebasedhdacinhibitorwmjj09inducescolorectalcancercelldeathbytargetingtubulinanddownregulatingsurvivin AT weijanhuang thehydroxamatebasedhdacinhibitorwmjj09inducescolorectalcancercelldeathbytargetingtubulinanddownregulatingsurvivin AT mengchiehyu thehydroxamatebasedhdacinhibitorwmjj09inducescolorectalcancercelldeathbytargetingtubulinanddownregulatingsurvivin AT chinhuichuang thehydroxamatebasedhdacinhibitorwmjj09inducescolorectalcancercelldeathbytargetingtubulinanddownregulatingsurvivin AT yafenhsu thehydroxamatebasedhdacinhibitorwmjj09inducescolorectalcancercelldeathbytargetingtubulinanddownregulatingsurvivin AT hsiuchenchen thehydroxamatebasedhdacinhibitorwmjj09inducescolorectalcancercelldeathbytargetingtubulinanddownregulatingsurvivin AT liangchiehchen thehydroxamatebasedhdacinhibitorwmjj09inducescolorectalcancercelldeathbytargetingtubulinanddownregulatingsurvivin AT shiuwenhuang thehydroxamatebasedhdacinhibitorwmjj09inducescolorectalcancercelldeathbytargetingtubulinanddownregulatingsurvivin AT mingjenhsu thehydroxamatebasedhdacinhibitorwmjj09inducescolorectalcancercelldeathbytargetingtubulinanddownregulatingsurvivin AT yuhanhuang hydroxamatebasedhdacinhibitorwmjj09inducescolorectalcancercelldeathbytargetingtubulinanddownregulatingsurvivin AT yuminhuang hydroxamatebasedhdacinhibitorwmjj09inducescolorectalcancercelldeathbytargetingtubulinanddownregulatingsurvivin AT weijanhuang hydroxamatebasedhdacinhibitorwmjj09inducescolorectalcancercelldeathbytargetingtubulinanddownregulatingsurvivin AT mengchiehyu hydroxamatebasedhdacinhibitorwmjj09inducescolorectalcancercelldeathbytargetingtubulinanddownregulatingsurvivin AT chinhuichuang hydroxamatebasedhdacinhibitorwmjj09inducescolorectalcancercelldeathbytargetingtubulinanddownregulatingsurvivin AT yafenhsu hydroxamatebasedhdacinhibitorwmjj09inducescolorectalcancercelldeathbytargetingtubulinanddownregulatingsurvivin AT hsiuchenchen hydroxamatebasedhdacinhibitorwmjj09inducescolorectalcancercelldeathbytargetingtubulinanddownregulatingsurvivin AT liangchiehchen hydroxamatebasedhdacinhibitorwmjj09inducescolorectalcancercelldeathbytargetingtubulinanddownregulatingsurvivin AT shiuwenhuang hydroxamatebasedhdacinhibitorwmjj09inducescolorectalcancercelldeathbytargetingtubulinanddownregulatingsurvivin AT mingjenhsu hydroxamatebasedhdacinhibitorwmjj09inducescolorectalcancercelldeathbytargetingtubulinanddownregulatingsurvivin |