The Hippo pathway is an evolutionary highly conserved signaling pathway that plays a crucial role in regulating cell proliferation, differentiation, and apoptosis in response to a wide range of extracellular as well as intracellular stimuli. The key downstream effector proteins of the Hippo pathways are the transcriptional co-activator YAP1 (yes-associated protein 1) and WWTR1 (WW domain-containing transcription regulator 1, aliases TAZ).
YAP/TAZ activity is regulated by its cellular localization. Unphosphorylated YAP/TAZ is located in the nucleus where it can interact with several transcription factors particularly the TEAD family of transcriptional factors (TEAD1-4) to regulate gene expression. In contrast, the activation of the Hippo pathway phosphorylates YAP/TAZ and determines its segregation and degradation in the cytoplasm.
Constitutive activation of YAP/TAZ due to gene amplification or loss-of-function of Hippo core kinase components MST1/2 or LATS1/2 kinase in mammals or their upstream activators such as NF2 has been observed in many tumor types, such as gastrointestinal cancer, lung cancer, and head and neck cancer. Several fusion proteins of YAP1 or WWTR1 are being discovered as cancer drivers. In addition, YAP/TAZ nuclear accumulation seems to be associated with poor cancer prognosis. Bound to its main functional partners, the transcription factor family TEAD, YAP/TAZ can promote tumorigenesis and cancer development by acting on several cellular mechanisms. It can promote cell proliferation and survival by upregulating the transcription of c-Myc and anti-apoptotic genes of the BCl-2 family. YAP/TAZ can also support cell growth by acting on cell metabolism as it has been described to affect both glucose uptake and glutamine biosynthesis.
YAP also retains some tumor suppressor features despite its ability to activate proliferation and anti-apoptotic genes. In response to DNA damage, YAP binds p73 to enhance the expression of pro-apoptotic genes. In addition, experimental evidence suggests that YAP loss or reduction in breast and colon cancer is associated with increased tumor growth and invasiveness.
Due to its ability to affect so many crucial cellular pathways, YAP/TAZ and the partnering TEADs are considered natural targets for anti-cancer drug discovery. However, further studies are needed to uncover the interactors and cellular stimuli that regulate its dual function as an oncogene and oncosuppressor to understand its role in cancer better.
This Research Topic aims to explore but is not limited to the following:
- extracellular and intracellular modulators of YAP/TAZ response in cancer
- molecular mechanisms that regulate YAP/TAZ tumor suppressor activity
- the role of Hippo kinase cascade independent of YAP/TAZ regulation in cancer
- novel interaction between YAP/TAZ and ncRNAs
- preclinical studies of YAP/TAZ and TEADs inhibitor compounds
- role and mechanism of YAP and TAZ fusion protein in cancer
- inter-linking of the Hippo pathway with other signaling pathways
Please note: manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic.
The Hippo pathway is an evolutionary highly conserved signaling pathway that plays a crucial role in regulating cell proliferation, differentiation, and apoptosis in response to a wide range of extracellular as well as intracellular stimuli. The key downstream effector proteins of the Hippo pathways are the transcriptional co-activator YAP1 (yes-associated protein 1) and WWTR1 (WW domain-containing transcription regulator 1, aliases TAZ).
YAP/TAZ activity is regulated by its cellular localization. Unphosphorylated YAP/TAZ is located in the nucleus where it can interact with several transcription factors particularly the TEAD family of transcriptional factors (TEAD1-4) to regulate gene expression. In contrast, the activation of the Hippo pathway phosphorylates YAP/TAZ and determines its segregation and degradation in the cytoplasm.
Constitutive activation of YAP/TAZ due to gene amplification or loss-of-function of Hippo core kinase components MST1/2 or LATS1/2 kinase in mammals or their upstream activators such as NF2 has been observed in many tumor types, such as gastrointestinal cancer, lung cancer, and head and neck cancer. Several fusion proteins of YAP1 or WWTR1 are being discovered as cancer drivers. In addition, YAP/TAZ nuclear accumulation seems to be associated with poor cancer prognosis. Bound to its main functional partners, the transcription factor family TEAD, YAP/TAZ can promote tumorigenesis and cancer development by acting on several cellular mechanisms. It can promote cell proliferation and survival by upregulating the transcription of c-Myc and anti-apoptotic genes of the BCl-2 family. YAP/TAZ can also support cell growth by acting on cell metabolism as it has been described to affect both glucose uptake and glutamine biosynthesis.
YAP also retains some tumor suppressor features despite its ability to activate proliferation and anti-apoptotic genes. In response to DNA damage, YAP binds p73 to enhance the expression of pro-apoptotic genes. In addition, experimental evidence suggests that YAP loss or reduction in breast and colon cancer is associated with increased tumor growth and invasiveness.
Due to its ability to affect so many crucial cellular pathways, YAP/TAZ and the partnering TEADs are considered natural targets for anti-cancer drug discovery. However, further studies are needed to uncover the interactors and cellular stimuli that regulate its dual function as an oncogene and oncosuppressor to understand its role in cancer better.
This Research Topic aims to explore but is not limited to the following:
- extracellular and intracellular modulators of YAP/TAZ response in cancer
- molecular mechanisms that regulate YAP/TAZ tumor suppressor activity
- the role of Hippo kinase cascade independent of YAP/TAZ regulation in cancer
- novel interaction between YAP/TAZ and ncRNAs
- preclinical studies of YAP/TAZ and TEADs inhibitor compounds
- role and mechanism of YAP and TAZ fusion protein in cancer
- inter-linking of the Hippo pathway with other signaling pathways
Please note: manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic.