Connexin43 pseudogene in breast cancer cells offers a novel therapeutic target.
Connexin43 (Cx43) is often deregulated in breast cancer tissue compared with normal adjacent tissue. Stable reexpression of Cx43 in cancer slows growth and renders the cells more sensitive to cytotoxic chemotherapeutics. Pseudogenes are often considered nonfunctional copies of DNA. The Cx43 pseudogene (PsiCx43) possesses all the features of an expressed gene and is exclusively transcribed in breast cancer cell lines and not in normal cells. PsiCx43 can be translated in vivo, and its protein exhibits growth-suppressive behavior similar to Cx43. We showed that PsiCx43 binds to the polyribosomes in breast cancer cells and that exogenous expression of PsiCx43 induces translational inhibition of Cx43. Furthermore, PsiCx43 is translated and binds more efficiently to the translational machinery than does Cx43 in an in vitro system. Following knockdown of PsiCx43 in breast cancer cells, we observed an increase in Cx43 RNA and protein. This results in increased cellular sensitivity to cytotoxic chemotherapy. Our results show that PsiCx43 acts as a posttranscriptional regulator of Cx43 in breast cancer cells, and that this represents an example of the regulation of genes by pseudogenes with potential therapeutic implications in cancer.
Department of Oncology, Segal Cancer Centre, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, and Department of Biochemistry and McGill Cancer Centre, McGill University, Montreal, Quebec, Canada H3T 1E2.
Andrew
A
Bier
Irene
I
Oviedo-Landaverde
Jing
J
Zhao
Yael
Y
Mamane
Mustapha
M
Kandouz
Gerald
G
Batist
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018031:Connexin 43 / Q000235:genetics* / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology; D011132:Polyribosomes; D011544:Pseudogenes; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D018031:Connexin 43; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D004317:Doxorubicin; D017239:Paclitaxel