The Noncanonical Role of Hippo Signaling in Cancer

Originally discovered in Drosophila, the Hippo pathway has emerged as an evolutionarily conserved signaling pathway that controls tissue growth and organ size in species ranging from insects to human. Unsurprisingly, dysregulation of Hippo pathway activity has been implicated in a broad spectrum of human cancers. While the prevailing view holds that the Hippo pathway suppresses tumor growth by inhibiting the oncogenic activity of the pathway effector Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ), recent studies have uncovered context-dependent tumor suppressor function of YAP/TAZ in several cancer types, including hematological malignancies, estrogen receptor (ER)-positive breast cancer, androgen receptor (AR)-positive prostate cancer, and Von Hippel-Lindau-deficient clear cell renal cell carcinoma (ccRCC). In this review, we explore the unconventional tumor-suppressive function of YAP/TAZ and the mechanisms through which they inhibit tumor growth, with an emphasis on recent findings in hormone-regulated cancers and ccRCC. Finally, we discuss the therapeutic implications of these emerging findings for cancer treatment.