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Fhit and Wwox loss-associated genome instability: A genome caretaker one-two punch
Morgan S Schrock1, Jenna R Karras1, Matthew J Guggenbiller1
1Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
Abstract:
Expression of Fhit and Wwox protein is frequently lost or reduced in many human cancers. In this report, we provide data that further characterizes the molecular consequences of Fhit loss in the initiation of DNA double-strand breaks (DSBs), and of Wwox loss in altered repair of DSBs. We show that loss of Fhit initiates mild genome instability in early passage mouse kidney cells, confirming that DNA damage associated with Fhit-deficiency is not limited to cancer cells. We also demonstrate that the cause of Fhit-deficient DSBs: thymidine deficiency-induced replication stress, can be resolved with thymidine supplementation in early passage mouse kidney cells before extensive genome instability occurs. As for consequences of Wwox loss in cancer, we show in a small panel of breast cancer cells and mouse embryonic fibroblasts that Wwox expression predicts response to radiation and mitomycin C, all agents that cause DSBs. In addition, loss of Wwox significantly reduced progression free survival in a cohort of ovarian cancer patients treated with platin-based chemotherapies. Finally, stratification of a cohort of squamous lung cancers by Fhit expression reveals that Wwox expression is significantly reduced in the low Fhit-expressing group, suggesting that loss of Fhit is quickly succeeded by loss of Wwox. We propose that Fhit and Wwox loss work synergistically in cancer progression and that DNA damage caused by Fhit could be targeted early in cancer initiation for prevention, while DNA damage caused by Wwox loss could be targeted later in cancer progression, particularly in cancers that develop resistance to genotoxic therapies.
Insights
Loss of Fhit protein initiates DNA double-strand breaks (DSBs) and genome instability, while Wwox loss affects DSB repair and predicts cancer treatment response. Their combined loss accelerates cancer progression.
Area of Science:
- Molecular biology
- Cancer research
- Genetics
Background:
- Loss of Fhit and Wwox protein expression is common in human cancers.
- Fhit deficiency is linked to DNA double-strand breaks (DSBs), and Wwox deficiency to altered DSB repair.
- Understanding these molecular events is crucial for cancer prevention and treatment.
Purpose of the Study:
- To characterize the molecular consequences of Fhit and Wwox loss.
- To investigate the role of Fhit and Wwox in DNA damage and repair.
- To explore their synergistic effects in cancer progression and therapeutic implications.
Main Methods:
- Assessing genome instability in Fhit-deficient mouse kidney cells.
- Evaluating the impact of thymidine supplementation on DSBs.
- Analyzing Wwox expression in relation to treatment response in breast and ovarian cancer cells.
- Correlating Fhit and Wwox expression in lung cancer patients.
Main Results:
- Fhit loss causes mild genome instability via thymidine deficiency-induced replication stress, which can be mitigated by thymidine supplementation.
- Wwox expression predicts response to DSB-inducing agents (radiation, mitomycin C) and is associated with progression-free survival in ovarian cancer patients.
- Loss of Fhit is followed by reduced Wwox expression in lung cancers, suggesting synergistic action.
Conclusions:
- Fhit and Wwox loss act synergistically in cancer progression.
- Targeting Fhit-deficiency early may prevent cancer initiation.
- Targeting Wwox loss later could overcome resistance to genotoxic therapies.