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NBM-T-BBX-OS01, Semisynthesized from Osthole, Induced G1 Growth Arrest through HDAC6 Inhibition in Lung Cancer Cells
Jih-Tung Pai1, Chia-Yun Hsu2, Kuo-Tai Hua3
1Division of Hematology and Oncology, Tao-Yuan General Hospital, Ministry of Health and Welfare, Taoyuan City 33004, Taiwan. jihtungpai@gmail.com.
Abstract:
Disrupting lung tumor growth via histone deacetylases (HDACs) inhibition is a strategy for cancer therapy or prevention. Targeting HDAC6 may disturb the maturation of heat shock protein 90 (Hsp90) mediated cell cycle regulation. In this study, we demonstrated the effects of semisynthesized NBM-T-BBX-OS01 (TBBX) from osthole on HDAC6-mediated growth arrest in lung cancer cells. The results exhibited that the anti-proliferative activity of TBBX in numerous lung cancer cells was more potent than suberoylanilide hydroxamic acid (SAHA), a clinically approved pan-HDAC inhibitor, and the growth inhibitory effect has been mediated through G1 growth arrest. Furthermore, the protein levels of cyclin D1, CDK2 and CDK4 were reduced while cyclin E and CDK inhibitor, p21Waf1/Cip1, were up-regulated in TBBX-treated H1299 cells. The results also displayed that TBBX inhibited HDAC6 activity via down-regulation HDAC6 protein expression. TBBX induced Hsp90 hyper-acetylation and led to the disruption of cyclin D1/Hsp90 and CDK4/Hsp90 association following the degradation of cyclin D1 and CDK4 proteins through proteasome. Ectopic expression of HDAC6 rescued TBBX-induced G1 arrest in H1299 cells. Conclusively, the data suggested that TBBX induced G1 growth arrest may mediate HDAC6-caused Hsp90 hyper-acetylation and consequently increased the degradation of cyclin D1 and CDK4.
Insights
A novel compound, TBBX, effectively halts lung cancer cell growth by inhibiting histone deacetylase 6 (HDAC6). This HDAC6 inhibition disrupts cell cycle regulation, offering a promising new strategy for lung cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Histone deacetylases (HDACs) inhibition is a validated strategy for cancer therapy.
- Targeting HDAC6 specifically may impact cell cycle regulation via heat shock protein 90 (Hsp90) pathways.
- Lung cancer remains a leading cause of cancer-related mortality, necessitating novel therapeutic approaches.
Purpose of the Study:
- To investigate the anti-cancer effects of semisynthesized NBM-T-BBX-OS01 (TBBX) derived from osthole.
- To elucidate the mechanism of TBBX-induced growth arrest in lung cancer cells, focusing on HDAC6.
- To compare the efficacy of TBBX with a clinically approved HDAC inhibitor, SAHA.
Main Methods:
- Treatment of lung cancer cell lines (H1299) with TBBX and SAHA.
- Cell cycle analysis (G1 arrest).
- Western blotting to assess protein expression (cyclin D1, CDK2, CDK4, cyclin E, p21Waf1/Cip1, HDAC6, Hsp90 acetylation).
- Assessment of protein-protein interactions (cyclin D1/Hsp90, CDK4/Hsp90).
- Proteasomal degradation assays.
- Rescue experiments using ectopic HDAC6 expression.
Main Results:
- TBBX demonstrated superior anti-proliferative activity compared to SAHA in lung cancer cells, inducing G1 growth arrest.
- TBBX treatment led to decreased levels of cyclin D1, CDK2, and CDK4, and increased levels of cyclin E and p21Waf1/Cip1.
- TBBX inhibited HDAC6 activity by down-regulating its protein expression, causing Hsp90 hyper-acetylation.
- This hyper-acetylation disrupted cyclin D1/Hsp90 and CDK4/Hsp90 interactions, promoting proteasomal degradation of cyclin D1 and CDK4.
- Restoring HDAC6 expression reversed the TBBX-induced G1 arrest.
Conclusions:
- TBBX effectively induces G1 growth arrest in lung cancer cells.
- The mechanism involves HDAC6 inhibition, leading to Hsp90 hyper-acetylation and subsequent degradation of key cell cycle regulators (cyclin D1, CDK4).
- TBBX represents a promising therapeutic agent for lung cancer, targeting HDAC6-mediated pathways.
