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

Abstract

Previous studies showed that YAP1 is over-expressed in hepatocellular carcinoma (HCC). Here we observed higher expression of Yap1/Ctgf axis in dysplastic nodules and HCC chemically-induced in F344 rats, genetically susceptible to hepatocarcinogenesis, than in lesions induced in resistant BN rats. In BN rats, highest increase in Yap1-tyr357, p73 phosphorylation and Caspase 3 cleavage occurred. In human HCCs with poorer prognosis (< 3 years survival after partial liver resection, HCCP), levels of YAP1, CTGF, 14–3–3, and TEAD proteins, and YAP1-14-3-3 and YAP1-TEAD complexes were higher than in HCCs with better outcome (> 3 years survival; HCCB). In the latter, higher levels of phosphorylated YAP1-ser127, YAP1-tyr357 and p73, YAP1 ubiquitination, and Caspase 3 cleavage occurred. Expression of stemness markers NANOG, OCT-3/4, and CD133 were highest in HCCP and correlated with YAP1 and YAP1-TEAD levels. In HepG2, Huh7, and Hep3B cells, forced YAP1 over-expression led to stem cell markers expression and increased cell viability, whereas inhibition of YAP1 expression by specific siRNA, or transfection of mutant YAP1 which does not bind to TEAD, induced opposite alterations. These changes were associated, in Huh7 cells transfected with YAP1 or YAP1 siRNA, with stimulation or inhibition of cell migration and invasivity, respectively. Furthermore, transcriptome analysis showed that YAP1 transfection in Huh7 cells induces over-expression of genes involved in tumor stemness. In conclusion, Yap1 post-translational modifications favoring its ubiquitination and apoptosis characterize HCC with better prognosis, whereas conditions favoring the formation of YAP1-TEAD complexes are associated with aggressiveness and acquisition of stemness features by HCC cells.

Overexpression of Yes‐associated protein and its association with clinicopathological features of hepatocellular carcinoma: A meta‐analysis

“…As shown in Table , heterogeneity analysis of the relationship between YAP expression and AFP indicated no significant heterogeneity among the studies. YAP is involved in many signalling pathways associated with HCC, but its actual role is unclear and worthy of investigation, especially because Simile's group reported that upregulation of YAP is related to HCC prognosis.…”

The Warburg Effect 97 Years after Its Discovery

“…YAP increases glycolysis [ 179 ] and supports the expression of Glut3, a known driver of a cancer stem cell phenotype, whose expression is elevated in cancer [ 18 , 182 ]. YAP/TAZ/TEAD and AP-1 form a complex that synergistically activates target genes controlling S-phase entry and mitosis [ 183 ]. In addition, in HepG2, Huh7, and Hep3B cells, forced YAP1 over-expression results in the expression of stem cell markers and increases cell viability [ 182 ].…”

p53 shades of Hippo

“…Activates p53 in response to mitotic stress 53,[142][143][144]149 Activates p53 in response to oncogenic Ras 117,118 Activates p53 in response to excess cholesterol 156 Activates p53 during mESC differentiation 52 YAP Loss of YAP induces p53 145,147,148 YAP represses ΔNp63 to inhibit lung cancer squamous cells transdifferentiation. 182 YAP-p73 promotes apoptosis 106,108-110, 132-134, 136,183 Yki inactivation induces Dmp53 119 p63 inhibits p73-YAPdependent apoptosis 22,137 YAP-tyr357-p73 is a marker for well differentiated HCC 85 Yki binds Dmp53 to promote apoptosis 131 YAP positively regulates p63 in epidermal stem cells 66 Locus is amplified in p53 null tumors [75][76][77]184,185 YAP positively regulates p63 in airway epithelium 71 p53 and YAP antagonistically regulate FOXM1 [186][187][188] YAP-p63 block differentiation in HNSCC 86 p53 transactivates 14-3-3σ, which inhibits YAP/TAZ 124,125 Binds p63 and prevents its degradation 88,89 YAP and p53 cooperate in apoptosis and senescence [126][127][128] Hyperactivation of YAP/TAZ induces p53 152,154 YAP and mutp53 cooperate in transformation 33,82 Mutp53 induces miRs that tar...…”

“…83 Interestingly, different post-translational modifications, which have been shown to govern YAP stability, may dictate the differentiation status of HCC. 84,85 Although hyperactivity of the YAP-TEAD functional axis predicts poor prognosis and stemness characteristics in HCC, tumors in which YAP is modified to interact with p73 (p-Y357) display more apoptotic markers and have better prognosis. 85 Thus, YAP can promote either tumor cell death or tumor-initiating properties, depending on its regulatory interactions with different members of the p53 family.…”

“…84,85 Although hyperactivity of the YAP-TEAD functional axis predicts poor prognosis and stemness characteristics in HCC, tumors in which YAP is modified to interact with p73 (p-Y357) display more apoptotic markers and have better prognosis. 85 Thus, YAP can promote either tumor cell death or tumor-initiating properties, depending on its regulatory interactions with different members of the p53 family. In the next sections, we will review in more detail the YAP-p73 pro-apoptotic module and try to delineate the mechanisms that modulate the apparently opposing cellular functions of YAP.…”