hCCR4/cNOT6 targets DNA-damage response proteins.
Radio and chemotherapy are the election options besides surgical resection, in cancer treatment. However, resistance to chemotherapy limits the effectiveness of therapy in the clinic. An improved knowledge of the mechanisms underlying the resistance to treatment would generate new therapeutic strategies. Genetic suppressor elements (GSEs) are short, biologically active, cDNA fragments that interfere with the function of their cognate gene. By selection of genetic suppressor elements (GSEs) conferring resistance to cisplatin, we identified the GSE11, that corresponds to the hCCR4/CNOT6 gene that mediates cellular sensitivity to the drug. Expression of GSE11-hCCR4 reduces hCCR4 protein levels in cells. Targeting hCCR4 with GSE11 or with siRNA, decreases sensitivity of mammalian cells to DNA-damaging agents. Overexpression of hCCR4 targets Chk2 following exposure to cisplatin, without interfering with the upstream ATM/ATR pathway, however histone gammaH2AX is strongly phosphorylated in these cells compared to control cells. Our results uncover a new function for a human protein involved in chemotherapy response. This finding introduces a new pharmacological target in the treatment of solid tumours.
Sanchez-Perez
I
I
Instituto de Investigaciones Biomédicas CSIC/UAM, Dpto. Modelos Experimentales de Enfermedades Humanas, Unidad de Oncologia Translacional. CIBER de Enfermadades Raras Valencia, Spain.
Manguan-Garcia
C
C
Menacho-Marquez
M
M
Murguía
J R
JR
Perona
R
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D005095:Exoribonucleases / Q000235:genetics / Q000378:metabolism*; D015723:Gene Library; D006657:Histones / Q000235:genetics*; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D020218:Response Elements
D000970:Antineoplastic Agents; C468783:H2AX protein, human; D006657:Histones; D034741:RNA, Small Interfering; D005095:Exoribonucleases; C534418:cNOT6 protein, human; D002945:Cisplatin