Dual degradation of aurora A and B kinases by the histone deacetylase inhibitor LBH589 induces G2-M arrest and apoptosis of renal cancer cells.
OBJECTIVE
This study is aimed at investigating antineoplastic efficacy of histone deacetylase inhibitor (HDACI) LBH589 on renal cell carcinoma (RCC) and elucidating the novel molecular mechanisms involved in growth arrest and apoptosis by targeting the important nonhistone molecules.


METHODS
We analyzed the growth-inhibitory effect of LBH589 on RCC by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in vitro and antitumor efficacy by xenograft experiments in vivo. To verify the associated molecular mechanisms involved in LBH589-mediated cell death and cell cycle progression by Western blotting and fluorescence-activated cell sorting analysis.


RESULTS
HDACI LBH589 induced degradation of both Aurora A and B kinases through a proteasome-mediated pathway by targeting HDAC3 and HDAC6. The dual degradation of Aurora A and B kinases mediated by LBH589 resulted in inducing G2-M arrest and apoptosis of renal cancer cell lines and our results also showed that LBH589 potently inhibited renal cancer cell growth in vitro and suppressed tumor formation in vivo. The Aurora A and B kinases and HDAC3 are overexpressed in the human RCC tumor tissues examined, which make them perfect targets for HDACI LBH589 treatment.


CONCLUSIONS
Our in vitro and in vivo data showed that LBH589 has potent anticancer effect of renal cancer cells. LBH589 and other HDACI treatment resulted in inducing G2-M arrest and apoptosis of renal cancer cells through degradation of Aurora A and B kinases by inhibition of HDAC3 and HDAC6. The clinical efficacy of LBH589 in the treatment of patients with metastatic RCC, especially those with high Aurora kinase and HDAC expression, is worthy of further investigation.
Cha
Tai-Lung
TL
Graduate Institute of Life Sciences, Tri-Service General Hospital, Taiwan, People's Republic of China. tlcha@ndmctsgh.edu.tw
Chuang
Mei-Jen
MJ
Wu
Sheng-Tang
ST
Sun
Guang-Huan
GH
Chang
Sun-Yran
SY
Yu
Dah-Shyong
DS
Huang
Shih-Ming
SM
Huan
Steven Kuan-Hua
SK
Cheng
Tse-Chou
TC
Chen
Tzu-Ting
TT
Fan
Pao-Luo
PL
Hsiao
Pei-Wen
PW
D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016195:G2 Phase; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D007211:Indoles; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000077767:Panobinostat; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000099186:Histone Deacetylase 3
D064096:Aurora Kinase A; D064127:Aurora Kinases; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat; D017346:Protein Serine-Threonine Kinases; D000099186:Histone Deacetylase 3; C576918:Aurka protein, mouse; C433811:HDAC6 protein, human