A novel study published in the journal Molecular Cell conducted at Karolinska Institutet highlights a new mechanism discovered that protects cancer cells from oncogene-induced stress and strategies to stop this mechanism.
Cancer is the condition of abnormal cellular growth with the capability of spreading to other parts of the body, interfering with normal bodily functions. According to a 2020 census, nearly 10 million people die of cancer every year.
Interplay Between FANCD2, CHK1 and FBX12 Affect Cancer Survival
According to the study, Fanconi anemia (FA) signaling pathway, which plays a crucial role in maintaining the integrity of our genetic material, becomes active when there are problems during DNA replication.
The study reveals that a protein called FANCD2, which is a key player in this pathway, undergoes a process called phosphorylation by another protein called CHK1. This phosphorylation event leads to the degradation of FANCD2 through a process guided by a protein called FBXL12.
This degradation helps to remove FANCD2 from sites where DNA replication has stalled.
This degradation of FANCD2 is important for ensuring smooth DNA replication, especially when there’s stress on the replication process caused by factors like CYCLIN E or certain drugs.
When the researchers tried to replace FANCD2 with versions that couldn’t undergo the specific type of modification the team at Karolinska identified that DNA replication didn’t proceed as it should.
Without FBXL12, FANCD2 gets stuck on the chromatin, causing problems during replication and leading to excessive DNA damage.
In human cancers, the team observed a connection between high levels of FBXL12, CYCLIN E, and the FA signaling pathway. Moreover, increased FBXL12 was seen to be associated with reduced survival in patients with breast tumors that express high levels of CYCLIN E.
Lastly, when the team reduced the levels of FBXL12, cancer cells were more susceptible to replication stress induced by oncogenes and were also more responsive to drugs that induce replication stress by inhibiting WEE1 protein (nuclear kinase).
Potential Future Benefits
The findings highlight that FBXL12 could be exploited as a potential weak point and a target for therapeutic intervention in cancers where CYCLIN E is overexpressed.
Understanding the link and interplay between FBXL12, CYCLIN E, and the Fanconi anemia pathway could contribute to personalized medicine approaches.
Patients with CYCLIN E-overexpressing cancers could undergo testing to assess their FBXL12 levels, potentially guiding treatment decisions and predicting treatment responses.
This discovery could also inspire the development of new drug classes that are capable of enhancing or inhibiting the various interactions, thus providing novel ways to control DNA replication.
The relation between these three factors could also lead to the development of diagnostic markers for early detection, prognosis assessment and treatment plans.
The team at Karolinska commented that further research by their lab will be focused on identifying compounds that target FANCD2 and FBXL12 signaling pathways to disrupt it.
