TAp63 Plays Role in Cancer Progression

In a new article published yesterday in Nature Communications, Moffitt Cancer Center researchers describe how the protein TAp63 controls levels of RNA molecules, which subsequently connects the activities of p53 and AKT to promote cancer progression. 

The researchers had previously shown that TAp63 functions as a tumor suppressor gene and that loss of its activity can lead to tumor development and spread. In follow-up studies, they wanted to determine the mechanism of how loss of TAp63 activity can lead to cancer in an effort to hijack these pathways to overcome p53 mutation in a therapeutic setting. Their investigations led them to make a connection between TAp63 and a type of RNA molecule called long noncoding RNA (lncRNA).

Through mouse model studies, they demonstrated that the lncRNAs stimulated cell migration and invasion, and high expression of two of the lncRNAs named TROLL-2 and TROLL-3 was associated with breast cancer progression. Importantly, downregulation of TROLL-2 and TROLL-3 inhibited the formation of several tumor types in mice including breast, melanoma and lung cancer. Additionally, the researchers found that TROLL-2 and TROLL-3 are highly expressed in a variety of metastatic human cancers, suggesting that these lncRNAs may be potential prognostic markers for tumor progression and targets for anti-cancer therapies.

The researchers also demonstrated that the tumor-promoting properties of the lncRNAs are dependent on the proteins WDR26 and NOLC1, which allow for shuttling in and out of the cell nucleus and regulation of cellular processes critical for cell survival. In cancer cells that lack TAp63 activity, TROLL-2 and TROLL-3 bind to WDR26 in the nucleus of the cell, preventing its interaction with NOLC1 and causing WDR26 to be shuttled out of the nucleus into the cytoplasm. In the cytoplasm, WDR26 stimulates the AKT signaling pathway, leading to increased cell migration and invasion and the promotion of tumor development.

"Our findings identify a crucial mechanism for the activation of the AKT pathway through TAp63-regulated lncRNAs and pave the way for more effective diagnostic tools for cancer progression and therapies against metastatic cancers with alterations in TP53 and hyperactivation of the PI3K/AKT pathway," lead researcher Elsa Flores concluded.