Cantharidin Inhibits Proliferation of Liver Cancer by Inducing DNA Damage via KDM4A-Dependent Histone H3K36 Demethylation

Abstract

Objective. To investigate the effect of cantharidin on DNA damage in hepatocellular carcinoma cells and its possible mechanism. Methods. Cell proliferation assay and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were used to analyze the effects of cantharidin on cell proliferation and apoptosis of hepatocellular carcinoma cells. The expression levels of DNA damage markers H2AX and P21 were analyzed by qRT-PCR. The expression of KDM4A and H3K36me3 was observed by western blot. The expression of KDM4A was regulated by siRNA or plasmid transfection. The effect of KDM4A on DNA damage induced by cantharidin in liver cancer was observed after overexpression and addiction of KDM4A. Results. Cantharidin can significantly inhibit the growth of hepatocellular carcinoma cells and induce apoptosis of hepatocellular carcinoma cells. Cantharidin enhances the chemotherapy sensitivity of liver cancer by targeting the upregulation of KDM4A and the regulation of DNA damage induced by H3K36me3. Overexpression of KDM4A enhances DNA damage induced by cantharidin in HCC. KDM4A silencing attenuated the damage of cantharidin to the DNA of HCC cells. Conclusion. Cantharidin can inhibit the growth and promote apoptosis of hepatocellular carcinoma cells. Meanwhile, cantharidin can induce DNA damage in HCC cells. Mechanism studies have shown that cantharidin induces DNA damage through the demethylation of KDM4A-dependent histone H3K36.

Hepatotoxic mechanism of cantharidin: insights and strategies for therapeutic intervention

“…In addition to targeted nano-delivery systems, antibodydrug conjugate technology offers a promising avenue by combining "specific" targeting and "efficient" killing of cancer cells (Anish et al, 2016). These drugs act like precision-guided "biological missiles" that can destroy cancer cells with precision, increase the therapeutic window, and reduce off-target side effects (Carmen et al, 2021). Research in this area may provide a significant breakthrough in the clinical use of CTDs, but further experimental validation is necessary.…”

“…Apoptosis is triggered by the activation of death receptors, such as Fas, TNFαR, DR3, DR4, and DR5, upon binding to their respective ligands. DNA damage, Ca 2+ homeostatic imbalance, and ERS can also initiate apoptosis (Chao et al, 2022). Upon activation of pro-apoptotic factor receptors, caspases cleave and activate downstream effector caspases, including caspase-3, -6, and -7 (Swanton et al, 1999).…”

Research progress of traditional Chinese medicine as sensitizer in reversing chemoresistance of colorectal cancer

“…Ginsenoside Rg3 responds to DNA damage by activating the VRK1/P53BP1 pathway, improving the efficiency of chemotherapy, reducing its side effects, and providing a new idea for cancer prevention and treatment ( 51 ). Cantharidin works by upregulating KDM4A and catalyzing the demethylation of histone H3K36me3 and inducing DNA damage, which in turn enhances the chemotherapy sensitivity ( 52 ). Cytotoxic drugs often result in serious neurotoxicity and other side effects while killing tumor cells, while Silibinin protects against cisplatin-induced neurotoxicity by reducing DNA damage and apoptosis ( 42 , 53 , 54 ).…”

Isolation of Peptide Inhibiting SGC-7901 Cell Proliferation from Aspongopus chinensis Dallas

“…For natural anti-cancer chemical screening, medicinal insects are important resources for active component isolation. It has been proven that cantharidin and its derivatives from meloid insects possess inhibitory effects on various cancer cells, such as laryngeal cancer, gastric cancer, leukemia, esophageal cancer, liver cancer, lung cancer, cervical carcinoma and prostatic cancer [ 4 , 5 , 6 , 7 , 8 , 9 ]. Bee venom and propolis (Apidae and Vespidae, Hymenoptera), which are traditionally utilized as medicines, also have inhibitory effects on the proliferation of leukemia, liver cancer, and esophageal carcinoma cells [ 10 , 11 ].…”