Metastases: a new level of control
Alternative splicing is a natural cellular process that helps cells perform a range of functions, from wound healing to embryonic development. Through alternative splicing, cells can synthesize a large number of proteins from a limited number of genes. In humans, about 95% of all genes function through alternative splicing. More recently, it has been proven that this process is associated with cancer – it can functionally control tumor metastasis.
In a previous study conducted by Baylor College of Medicine, it was shown that one of the two forms of CD44 protein (CD44s), which can be obtained by alternative splicing, contributes to the survival of cancer cells. In a new study, the same group demonstrated how alternative splicing promotes cancer metastasis. To do this, a search was performed for proteins that regulate alternative splicing events associated with metastasis.
AKAP8 protein helps to keep cancer cells in a non-metastatic state
The researchers screened the cells in search of proteins that function as alternative splicing modulators that prevented cell metastasis. They identified a number of proteins that are potentially key in the regulation of tumor metastasis, and settled on AKAP8.
This protein has been studied in animal models of metastatic breast cancer from human cancer cells. Depletion of AKAP8 protein in cancer cells has been found to contribute to breast cancer metastasis. In addition, the presence of an external source of AKAP8 inhibited metastasis.
Thus, the results confirm that the AKAP8 protein is an important regulator of alternative splicing, the products of which are associated with tumor metastasis. It is not only able to predict the outcome of metastatic breast cancer in patients, but can also inhibit the progression of metastatic breast cancer in animal models.
The researchers then set out to determine how AKAP8 mediates its metastasis inhibition effects. They found that, in addition to modulating alternative splicing of CD44, AKAP8 also regulates alternative splicing of the CLSTN1 protein. Of the two forms of CLSTN1 – CLSTN1S and CLSTN1L – AKAP8 changed the balance towards the production of the first, and this was due to the prevention of the transition of cells to a metastatic state. Previously, this function of CLSTN1 was not known.
The authors believe that alternative splicing modulators are involved in the fine balancing of many proteins, such as CD44 and CLSTN1. Two types of modulators play a role in maintaining balance. One type, such as AKAP8, modulates alternative splicing towards the production of proteins that help cells stay in a normal state. Another type stimulates the synthesis of proteins that promote metastatic transformation. If the balance is disturbed, the progression of the tumor can be accelerated. The mechanisms of maintaining balance and the factors that disrupt it may help to understand a new level of regulation of tumor metastasis and obtain information necessary for the treatment of metastatic cancer.
Article X.Hu et al. The RNA-binding protein AKAP8 suppresses tumor metastasis by antagonizing EMT-associated alternative splicing is published in the journal Nature Communications.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of Baylor College of Medicine: Protein AKAP8 suppresses breast cancer metastasis.