Tumor suppressor protein ARID1A necessary to maintain the coherence of telomeres and correct segregation of chromosomes following DNA replication. This discovery, reported by researchers at the Wistar Nature Communications, indicate that ARID1A-mutated cells undergo gross genomic changes that are incompatible with the survival and explains the absence of genomic instability, typical for ARID1A-mutated cancers.
ARID1A gene is one of the most commonly mutated gene in human cancer, a mutation frequency, reaching 60% at a transparent cell ovarian disease, known for its poor response to chemotherapy. ARID1A performs fundamental functions of tumor suppression, loss of which contributes to the development of cancer.
"Although it is known that ARID1A acts as a protector of the genome integrity, types of high-frequency ARID1A mutations in cancer are not usually associated with genomic instability, as measured by changes in the copy number of genes," - said Rugang Zhang, Ph.D., deputy director of the Cancer Center Wistar Institute professor and head of the joint program on the expression and regulation of genes and the lead author of the new study.
Zhang and his colleagues have shown that ARID1A is required for telomere cohesion, because it controls the expression of STAG1, the protein component of the complex cohesin. In fact, ablation ARID1A in vitro function leads to suppression STAG1 and hence defects telomeres and chromosomal changes during cell division.
Importantly, the cells with inactivated ARID1A showed reduced ability to form colonies in the analysis, which is used as a measure of survival of cancer cells during cell division, which indicates that chromosomal defects that occur in the absence of ARID1A, are not compatible with the survival of the cells.
"We have identified a selection process that enriches the cancer cells that lack genomic instability", - said Zhang. "This may explain the apparent paradox of the stored genomic stability ARID1A-mutated cancer."
"It is interesting that ARID1A inactivation correlates with poor response to chemotherapy, aimed at cell division, such as paclitaxel," - said Bo Zhao, Ph.D., first author of the study and a postdoctoral researcher in Zhang lab. "Our findings may partly explain why transparent ovarian cancer usually responds poorly to chemotherapy for this class."