TEADs serve as potential prognostic biomarkers and targets for human gastric cancer

Wang, Meng-huan; Bing-zhi, LI; Chen, Yue; Wang, Jie

doi:10.1186/s12876-022-02386-8

Cited by 8 publications

(3 citation statements)

References 37 publications

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“…TEAD4 mRNA was upregulated in patients with GC, and a significant enrichment (~7%) was predicted in gastric intestinal-type adenocarcinoma. Increased TEADs (TEAD1-4) mRNA expressions were significantly correlated with overall survival (OS), progression-free survival (PFS), and post-progression survival (PPS) in gastric cancer (GC) patients [38]. A pan-cancer differential TEADs expression identified a high expression of TEAD1, TEAD2, TEAD3, and TEAD4 in 3, 6, 5, and 12 types of cancer tissues, respectively.…”

Section: Teads Withhold the Oncogenic Driver Seat In Various Types Of...mentioning

confidence: 99%

Hippo Signaling at the Hallmarks of Cancer and Drug Resistance

Kumar,

Hong

2024

Cells

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Originally identified in Drosophila melanogaster in 1995, the Hippo signaling pathway plays a pivotal role in organ size control and tumor suppression by inhibiting proliferation and promoting apoptosis. Large tumor suppressors 1 and 2 (LATS1/2) directly phosphorylate the Yki orthologs YAP (yes-associated protein) and its paralog TAZ (also known as WW domain-containing transcription regulator 1 [WWTR1]), thereby inhibiting their nuclear localization and pairing with transcriptional coactivators TEAD1-4. Earnest efforts from many research laboratories have established the role of mis-regulated Hippo signaling in tumorigenesis, epithelial mesenchymal transition (EMT), oncogenic stemness, and, more recently, development of drug resistances. Hippo signaling components at the heart of oncogenic adaptations fuel the development of drug resistance in many cancers for targeted therapies including KRAS and EGFR mutants. The first U.S. food and drug administration (US FDA) approval of the imatinib tyrosine kinase inhibitor in 2001 paved the way for nearly 100 small-molecule anti-cancer drugs approved by the US FDA and the national medical products administration (NMPA). However, the low response rate and development of drug resistance have posed a major hurdle to improving the progression-free survival (PFS) and overall survival (OS) of cancer patients. Accumulating evidence has enabled scientists and clinicians to strategize the therapeutic approaches of targeting cancer cells and to navigate the development of drug resistance through the continuous monitoring of tumor evolution and oncogenic adaptations. In this review, we highlight the emerging aspects of Hippo signaling in cross-talk with other oncogenic drivers and how this information can be translated into combination therapy to target a broad range of aggressive tumors and the development of drug resistance.

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Section: Teads Withhold the Oncogenic Driver Seat In Various Types Of...mentioning

confidence: 99%

Hippo Signaling at the Hallmarks of Cancer and Drug Resistance

Kumar,

Hong

2024

Cells

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“…Salvador adaptor protein (SAV), which contains two protein-protein interaction modules known as WW domains, is considered to function as a scafolding protein for the mammalian Hippo pathway [4]. Salvador homologue 1 (SAV1), also known as WW45, is the human homolog of Salvador that couples mammalian Ste20-like 1 and 2 kinases (MST1/2) to large tumor suppressor kinases 1 and 2 (LATS1/ 2) to form the Hippo signaling pathway [5]. As an adaptor protein, SAV1 acts as a coactivator of MST1/2 kinases and can directly bind to MST1/2 and induce the kinase cascade via promoting the phosphorylation of MST 1/2, LATS 1/2, yes-associated protein (YAP), and/or transcriptional coactivation with PDZ-binding motif (TAZ).…”

Section: Introductionmentioning

confidence: 99%

Novel KDM2B/SAV1 Signaling Pathway Promotes the Progression of Gastric Cancer

Song

Chen

et al. 2023

Genetics Research

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Salvador homologue 1 (SAV1), which is reported to act as a tumor suppressor in different types of cancer, is one of the key components of the Hippo pathway. However, the expression and mechanisms of SAV1 in the development and progression of gastric cancer (GC) remain to be elucidated. Immunohistochemistry (IHC) was performed in the present study to assess the expression levels of SAV1 and lysine-specific demethylase 2B (KDM2B) in GC tissues. The biological effects of SAV1 on GC cell proliferation, migration, and invasion were studied in vitro. KDM2B transcriptionally regulates SAV1 expression in several GC cell lines, and molecular experiments were performed to investigate underlying mechanisms. The expression level of SAV1 was significantly decreased in GC tissues and cell lines, negatively associated with tumor invasion depth, lymph node metastasis, and TNM stage, and positively associated with the overall survival of patients with GC. SAV1 overexpression inhibited the proliferation, migration, and invasion of GC cells. Further mechanistic studies revealed that KDM2B transcriptionally regulated SAV1 expression and further regulated the Hippo signaling pathway. To conclude, the present study demonstrated that KDM2B transcriptionally regulated SAV1 expression and promoted GC progression.

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“…5 The activated LATS1/2 phosphorylate YAP/TAZ, leading to their retention in the cytoplasm and subsequent degradation via the ubiquitin−proteasome system, thereby limiting tissue growth and cell proliferation. 4 Dysregulation of the Hippo signaling pathway has been implicated in various carcinomas, including lung, 6 gastric, 7 prostate, 8 and colorectal cancers, 9 and is associated with poor outcomes. In cancer cells, the dephosphorylated YAP/TAZ translocate into the nucleus, bind to TEAD, and drive the transcriptions of target oncogenes critical for cancer development.…”

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confidence: 99%

Design, Synthesis, and Bioevaluation of Transcriptional Enhanced Assocciated Domain (TEAD) PROTAC Degraders

Li,

Ge,

Lin

et al. 2024

ACS Med. Chem. Lett.

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Dysregulation of the Hippo pathway has been observed in various cancers. The transcription factor TEAD, together with its coactivators YAP/TAZ, plays a crucial role in regulating the transcriptional output of the Hippo pathway. Recently, extensive research has focused on small molecule inhibitors targeting TEAD, but studies on TEAD degraders are comparatively rare. In this study, we designed and synthesized a series of TEAD PROTACs by connecting a pan-TEAD inhibitor with the CRBN ligand thalidomide. A representative compound, 27, exhibited potent antiproliferative activity against NF2-deficient NCI-H226 cells. It dose-dependently induced TEAD degradation dependent on CRBN and proteasome system and decreased key YAP target genes CYR61 and CTGF expressions in NCI-H226 cells. Further degradation selectivity studies revealed that 27 exhibited more potent activity against TEAD2 compared to those of the other three family members in Flag-TEADs transfected 293T cells. Therefore, 27 may serve as a valuable tool for advancing biological studies related to TEAD2.

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TEADs serve as potential prognostic biomarkers and targets for human gastric cancer

Cited by 8 publications

References 37 publications

Hippo Signaling at the Hallmarks of Cancer and Drug Resistance

Hippo Signaling at the Hallmarks of Cancer and Drug Resistance

Novel KDM2B/SAV1 Signaling Pathway Promotes the Progression of Gastric Cancer

Design, Synthesis, and Bioevaluation of Transcriptional Enhanced Assocciated Domain (TEAD) PROTAC Degraders

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