The YAP–TEAD4 complex promotes tumor lymphangiogenesis by transcriptionally upregulating CCBE1 in colorectal cancer

NAT10‐mediated ac4C‐modified ANKZF1 promotes tumor progression and lymphangiogenesis in clear‐cell renal cell carcinoma by attenuating YWHAE‐driven cytoplasmic retention of YAP1

“…[ 49 ] revealed that activation of the Wnt signaling heightened the secretion of VEGFC, thereby fostering the lymphatic metastasis of bladder cancer. Previous independent investigations have revealed that YAP1, the core effector of the Hippo pathway, regulated lymphangiogenesis by the VEGFC/D‐VRGFR3 signaling pathway [ 50 , 51 ]. Consistent with these findings, we discovered that NAT10‐driven nuclear translocation of YAP1 led to an upregulation of VEGFC/D expression, consequently promoting lymphangiogenesis in ccRCC.…”

“…While the NAT10‐YAP1 axis concurrently upregulated the mRNA and protein levels of VEGFC/D, the increase in VEGFD concentration induced by NAT10 overexpression in the CM was significantly more pronounced than that observed for VEGFC. This highlighted a possibility that the NAT10‐regulated Hippo signaling might selectively participate in the maturation process of either VEGFC or VEGFD [ 51 ]. In summary, the present study elucidated a molecular mechanism of tumor lymphangiogenesis in ccRCC, providing new therapeutic targets for inhibiting the progression and lymphatic metastasis of renal cancer.…”

The potential of BRD4 inhibition in tumour mechanosignaling

“…7 As a result of the fact that BRD4 demonstrates YAP/TAZindependent transcriptional activity, combined YAP/TAZ/BRD4 targeting could also address the full extent of the tumour mechanosignaling-engaged impact on cancer progression. 9 As a proof of concept, preclinical data highlight the efficacy of BRD4 inhibition when YAP/TAZ/TEAD negative regulators lose their function, implying that BRD4 suppression could be an alternative therapeutic strategy to diminish YAP/TAZ-induced gene expression. 10 In conclusion, although the application of BETi in the clinic seems promising, their full potential has not yet been realized due to the lack of satisfactory predictive biomarkers.…”

“…Furthermore, BRD4 is capable of tethering to collagen‐ and calcium‐binding epidermal growth factor domain‐containing protein 1 ( CCBE1 ) enhancers, a known booster of tumour lymphangiogenesis. This interaction is sustained even when mechanosensitive YAP/TAZ are absent, implying that there is a mechanism for BRD4‐mediated modulation of CCBE1 transcription, which is independent of the YAP/TAZ‐associated transcriptional enhancer factor TEF‐3 (TEA domain family member 4, TEAD4) complex 9 . In head and neck squamous cell carcinoma (HNSCC), BRD4 interacts with the YAP1/TAZ/TEAD transcriptional complex to facilitate expression of oncogenes.…”

“…Therefore, administration of BETi should be evaluated in preclinical and clinical studies to overcome resistance or inefficacy of YAP/TAZ/TEAD inhibitors 7 . As a result of the fact that BRD4 demonstrates YAP/TAZ‐independent transcriptional activity, combined YAP/TAZ/BRD4 targeting could also address the full extent of the tumour mechanosignaling‐engaged impact on cancer progression 9 . As a proof of concept, preclinical data highlight the efficacy of BRD4 inhibition when YAP/TAZ/TEAD negative regulators lose their function, implying that BRD4 suppression could be an alternative therapeutic strategy to diminish YAP/TAZ‐induced gene expression 10 …”