STK4 Inhibition Promotes YAP1-Mediated Apoptosis in Hematologic Cancers

Oncogene-induced DNA damage is prevalent in precancerous epithelial lesions, but malignant progression does not occur until apoptosis is suppressed by p53 inactivation. However, the presence of chronic DNA damage is less well established in hematologic malignancies, and the rarity of TP53 mutations and deletions in these cancers suggests that p53-independent pathways may be responsible for the evasion of apoptosis. Cottini and colleagues report that the majority of multiple myeloma cell lines and primary samples showed signs of persistent DNA damage but not significant cell death, and were characterized by high nuclear levels of the ABL1 kinase, which promotes apoptosis in response to DNA damage by interacting with the Hippo pathway effector YAP1 and the p53 homolog p73. In contrast with epithelial tumors in which YAP1 is often overexpressed, YAP1 was frequently downregulated or focally deleted in multiple myeloma and other hematologic cancers, and reduced YAP1 expression correlated with poor clinical outcome, suggesting that YAP1 may have tumor- suppressive functions in certain contexts. Consistent with these findings, reintroduction of YAP1 in multiple myeloma, leukemia, or lymphoma cells with low YAP1 expression or YAP1 deletion induced cell death that was dependent on ABL1-mediated phosphorylation of YAP1, binding of YAP1 to p73, and induction of proapoptotic p73 target gene expression. Given that the cytoplasmic kinase STK4 has previously been shown to reduce YAP1 levels, the authors tested the effect of silencing STK4 in multiple myeloma, leukemia, and lymphoma cells with low YAP1 levels and found that STK4 suppression restored YAP1 expression and induced apoptosis both in vitro and in vivo. Together, these results provide insight into how hematologic malignancies evade apoptosis despite ongoing DNA damage as well as a rationale for the development of STK4 inhibitors for treatment of blood cancers with low YAP1 expression and ongoing DNA damage.

Cottini F, Hideshima T, Xu C, Sattler M, Dori M, Agnelli L, et al. Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers. Nat Med 2014 May 11 [Epub ahead of print].