title: CHFR suppression by hypermethylation sensitizes endometrial cancer cells to paclitaxel.
abstract: OBJECTIVE
  Impairment of a cell cycle checkpoint is often associated with sensitivity to chemotherapeutic drugs. Here, we studied the correlations between the checkpoint with forkhead-associated and ring finger (CHFR) gene expression and responses to paclitaxel in endometrial cancer cells.
  
  
  METHODS
  We cultured 6 endometrial cancer cell lines exposed to paclitaxel, studied the cell cytotoxicity, cell cycle distribution, CHFR expression, and methylation status before and after a demethylation agent (5-aza) treatment. CHFR was silenced by small interfering RNA (siRNA). Then we examined tumor growth and CHFR expression with paclitaxel alone or combined with 5-aza pretreatment in vivo.
  
  
  RESULTS
  We found that HEC-1B, RL-952, and AN3CA cells were sensitive to paclitaxel. Moreover, CHFR was weakly expressed in these cells, whereas paclitaxel-resistant cells (ISH, HEC-1A, and KLE) had high CHFR expression. Then we found that restored expression of CHFR by demethylation decreased the sensitivity to paclitaxel in AN3CA cells. In addition, cells with CHFR demethylation resulted in G2/M phase arrest that induced to paclitaxel resistance. These results were confirmed again in small interfering RNA-transfected HEC-1A cells. Furthermore, in nude mice model, restored expression of CHFR by demethylation inhibited tumor growth and decreased sensitivity to paclitaxel.
  
  
  CONCLUSIONS
  Our data suggest that CHFR suppression regulated by hypermethylation may sensitize endometrial cancer cells to paclitaxel, and CHFR may be a promising marker to predict the response of endometrial cancer to paclitaxel.
authors.affiliation: Department of Obstetrics and Gynecology, Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Wang
authors.forename: Yuebo
authors.initials: Y
authors.lastname: Yang
authors.forename: Chengfang
authors.initials: C
authors.lastname: Xu
authors.forename: Lan
authors.initials: L
authors.lastname: Xiao
authors.forename: Huimin
authors.initials: H
authors.lastname: Shen
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Tian
authors.initials: T
authors.lastname: Li
authors.forename: Xiaomao
authors.initials: X
authors.lastname: Li
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D019175:DNA Methylation; D017931:DNA Primers; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D020868:Gene Silencing; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D000075223:Poly-ADP-Ribose Binding Proteins; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D044767:Ubiquitin-Protein Ligases
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D017931:DNA Primers; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases; D017239:Paclitaxel