In Vitro The Anticancer Effects Of Histone Deacetylase Inhibitors On Human Renal Cell Carcinoma Cells And Its Possible Molecular Mechanisms

BackgroundRenal cell carcinoma is the third leading cause of death among urologic tumors,accounting for2%of adult malignancies. In spite of improved diagnostic techniques,metastatic lesions are still found in30%of patients who have renal cell carcinoma.Surgery is the mainstay of treatment for early and locally advanced renal cell carcinoma. Itis relatively resistant to radiation therapy and chemotherapy for advanced renal carcinoma.Advanced renal cell carcinoma could not be operated and is resistant to availablechemotherapy. Therefore, developing novel new agents is urgently needed.Histone deacetylases and histone acetylases are responsible for deacetylating andacetylating, respectively, the lysine residues located at the amino-terminal tails of histones.Gene regulation is maintained through chromatin remodeling by the opposite actions ofhistone deacetylases and histone acetylases. Alteration in the balance of these enzymes canresult in gene silencing, malignant transformation, cell growth, and aberrant cell signaling.Deacetylation-associated with transcription repression and abnormal recruitment ofhistone acetylase contribute to carcinogenesis. Thus, histone acetylases are considered asimportant cancer targets and histone acetylase inhibitors are becoming a new class ofpromising anticancer drugs.ObjectiveTo study effect of histone deacetylase inhibitors Trichostatin A and panobinostat on human renal cell carcinoma OS-RC-2cells in vitro and to explore the underlyingmolecular mechanism.MethodOS-RC-2cells were treated by LBH589or TSA and/or SP600125and followed bycell viability assay using MTT. Flow cytometry(FCM) was used to quantify thedistribution of OS-RC-2cells in different phase of cell cucle or apoptosis. The expressionsof c-Jun, p-c-Jun, Bcl-2, and Bax were quantified by Western blotting.ResultTSA and LBH589inhibited the growth of OS-RC-2cells in a dose-andtime-dependent manner. TSA (1μM) or LBH589(50nM) blocked the G2/M transitionand induced apoptosis of OS-RC-2cells（p<0.05）. TSA and LBH589significantlyincreased the protein level of phosphorylated c-Jun（p<0.05）. TSA also induced theprotein level of Bax, but decreased Bcl2（p<0.05）. JNK inhibitor SP600125partiallyattenuated the growth inhibitory effects of TSA in human renal cell carcinoma OS-RC-2cells. SP600125also partially prevented the TSA-induced phosphorylation of c-Jun andBax as well as the induction of Bcl2（p<0.05）.ConclusionHDACi inhibited the growth of OS-RC-2cells, arrested cells at G2/M phasetransition and induced apoptosis of OS-RC-2cells. TSA induced human renal cellcarcinoma cells apoptosis through p-JNK activation. P-JNK pathway have a role inTSA-induced death of human renal cell carcinoma OS-RC-2cells.