An Imbalance in TAZ and YAP Expression in Hepatocellular Carcinoma Confers Cancer Stem Cell–like Behaviors Contributing to Disease Progression

Abstract

Transcriptional coactivator with PDZ-binding motif (TAZ) and yes-associated protein (YAP) are equivalently placed downstream effectors of the Hippo pathway with oncogenic roles in human cancers. However, the expression profiles of TAZ/YAP differ depending on the cancer cell type, suggesting that these proteins have different roles during cancer progression, yet no studies have examined the biologic significance of the balance between TAZ and YAP expression levels. Here we examined the functional roles of TAZ/YAP in hepatocellular carcinoma progression. We found that TAZ, but not YAP, was predominantly expressed in HCC. TAZ knockdown under normal conditions attenuated cell growth in HCC cells; however, TAZ knockdown combined with 5-fluorouracil treatment significantly increased chemoresistance compared with control cells. Notably, TAZ knockdown induced compensatory YAP expression and was accompanied by upregulation of CD90, a HCC-specific cancer stem cell marker. Continuous treatment with 5-fluorouracil also induced YAP expression and promoted tumor formation in vivo. Conversely, double knockdown of TAZ/YAP reduced chemoresistance and tumorigenicity. Moreover, YAP knockdown aggravated HCC cell growth to a greater degree than TAZ knockdown, and YAP overexpression was strongly associated with poor prognoses in patients with HCC. Collectively, these studies demonstrate that TAZ and YAP exhibit different functional roles in cancer progression, and a shift to predominant YAP expression upon TAZ depletion conferred cancer stem cell-like properties including chemoresistance and tumorigenicity in HCC. Therefore, targeting of both TAZ/YAP will be required for a complete antitumor response in HCC.

YAP/TAZ Are Essential for TGF-β2–Mediated Conjunctival Fibrosis

“…52 In hepatocellular carcinoma, TAZ is predominantly expressed under normal conditions, but a switch into YAP-dominant expression is thought to be a key step to acquire a cancer stem-like property. 53 Moreover, YAP-and TAZdeficient mice show different phenotypes: YAP-deficient mice are embryonic lethal, whereas TAZ knockout mice are viable. [54][55][56] The differential functions of YAP and TAZ can be explained by the differential binding partners.…”

Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease

“…In the same sample collection, nonetheless, YAP overexpression was associated with HCC poor prognosis, and a compensatory YAP upregulation following TAZ depletion conferred cancer stem cell-like properties to HCC cells [18]. …”

Monopolar spindle-one-binder protein 2 regulates the activity of large tumor suppressor/yes-associated protein to inhibit the motility of SMMC-7721 hepatocellular carcinoma cells

“…It is widely accepted that the phosphorylation of YAP results in its cytoplasmic retention and reduced nuclear YAP and transcriptional activity of TEA domain family (14)(15)(16). Therefore, RT-qPCR was performed in order to analyze the expression of CTGF and CYR61, two well-characterized YAP target genes (18,19), in SMMC-7721 cells MOB2 overexpressing-cells, MOB2 knockout cells and their corresponding vector control cells. It was revealed that the overexpression of MOB2 significantly decreased the expression of CTGF and CYR61, while the knockout of MOB2 significantly promoted the transcription of CTGF and CYR61 compared with the levels in their corresponding vector control cells (P<0.05; Fig.…”