| Autor: |
Gantchev J; Research Institute of McGill University Health Centre, Montreal, QC H4A 3J1, Canada., Messina-Pacheco J; Research Institute of McGill University Health Centre, Montreal, QC H4A 3J1, Canada.; Department of Pathology, McGill University, Montreal, QC H4A 3J1, Canada., Martínez Villarreal A; Research Institute of McGill University Health Centre, Montreal, QC H4A 3J1, Canada., Ramchatesingh B; Research Institute of McGill University Health Centre, Montreal, QC H4A 3J1, Canada., Lefrançois P; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada., Xie P; Division of Dermatology, Department of Medicine, McGill University Health Centre, Montreal, QC H4A 3J1, Canada., Amar L; Faculty of Medicine, McGill University, Montreal, QC H3G 2M1, Canada., Xu HH; Faculty of Medicine, Laval University, Quebec City, QC G1V 0A6, Canada., Raveendra K; Faculty of Science, McGill University, Montreal, QC H3A 0G5, Canada., Sikorski D; Faculty of Medicine, McGill University, Montreal, QC H3G 2M1, Canada., Guerra Ordaz DJ; Research Institute of McGill University Health Centre, Montreal, QC H4A 3J1, Canada., Gill RPK; Research Institute of McGill University Health Centre, Montreal, QC H4A 3J1, Canada., Lambert M; Research Institute of McGill University Health Centre, Montreal, QC H4A 3J1, Canada., Litvinov IV; Research Institute of McGill University Health Centre, Montreal, QC H4A 3J1, Canada.; Division of Dermatology, Department of Medicine, McGill University Health Centre, Montreal, QC H4A 3J1, Canada. |
| Abstrakt: |
Genomic instability is a prominent hallmark of cancer, however the mechanisms that drive and sustain this process remain elusive. Research demonstrates that numerous cancers with increased levels of genomic instability ectopically express meiosis-specific genes and undergo meiomitosis, the clash of mitotic and meiotic processes. These meiotic genes may represent novel therapeutic targets for the treatment of cancer. We studied the relationship between the expression of the meiosis protein HORMAD1 and genomic instability in squamous cell carcinomas (SCCs). First, we assessed markers of DNA damage and genomic instability following knockdown and overexpression of HORMAD1 in different cell lines representing SCCs and epithelial cancers. shRNA-mediated depletion of HORMAD1 expression resulted in increased genomic instability, DNA damage, increased sensitivity to etoposide, and decreased expression of DNA damage response/repair genes. Conversely, overexpression of HORMAD1 exhibited protective effects leading to decreased DNA damage, enhanced survival and decreased sensitivity to etoposide. Furthermore, we identified a meiotic molecular pathway that regulates HORMAD1 expression by targeting the upstream meiosis transcription factor STRA8. Our results highlight a specific relationship between HORMAD1 and genomic instability in SCCs, suggesting that selectively inhibiting HORMAD1, possibly, through STRA8 signaling, may provide a new paradigm of treatment options for HORMAD1-expressing SCCs. |
