The Involvement of WDHD1 in the Occurrence of Esophageal Cancer as a Downstream Target of PI3K/AKT Pathway

Abstract

Esophageal cancer is one of the most common malignant tumors in the world, which is characterized by high incidence, strong invasiveness, high mortality, and poor prognosis. At present, the therapies include surgery, endoscopic resection, radiotherapy and chemotherapy, targeted therapy, and immunotherapy. The five-year survival rate of esophageal cancer has not been significantly improved, although the medical level has been continuously improved and the management and application of different therapies have been improved day by day. At present, an abnormal gene expression is still regarded as an important factor in the occurrence and development of esophageal cancer. WD repeat and HMG-box DNA binding protein 1(WDHD1), as a key gene, plays an important role in the occurrence of esophageal cancer. It is known that the protein encoded by WDHD1 is the downstream target of the PI3K/AKT pathway. When PI3Ks is activated by extracellular signals, PI(4,5)P2 on the inner side of the plasma membrane will be converted into PI(3,4,5)P3. Then, PI(3,4,5)P3 can be converted into PI(3,4)P2,PI(4)P and PI(3)P by dephosphorylation of some regulatory factors. PI(3,4,5)P3 recruited AKT to the plasma membrane and combined with its pH domain, resulting in conformational change of AKT. Subsequently, AKT was completely activated by PDK1 and PDK2 and begins to move to the cytoplasm and nucleus. In this process, AKT continuously phosphorylates downstream substrates. WDHD1, as a downstream target of AKT, is also phosphorylated and induces DNA replication. Besides the abnormal regulation of cells by other downstream targets of AKT, it also becomes a potential pathway that may eventually lead to the occurrence of esophageal cancer.

Integrative bioinformatics analysis of WDHD1: a potential biomarker for pan-cancer prognosis, diagnosis, and immunotherapy

“…Their subsequent cell experiment illustrated that WDHD1 acted as a pivotal cell cycle regulator and an essential component of the phosphoinositide-3-kinase-protein kinase B (PI3K)/Akt pathway. Similar conclusions were reached by Xian et al who suggested that WDHD1 might be an irreplaceable tumor factor in the case of esophageal cancer [ 18 , 69 ]. Concerning CHOL, inhibiting WDHD1 repressed cell migration and invasion while promoting cell apoptosis [ 63 ].…”

WD Repeat and HMG Box DNA Binding Protein 1: An Oncoprotein at the Hub of Tumorigenesis and a Novel Therapeutic Target

“…In the study, they performed experiments involving immunoprecipitation of labeled WDHD1 and recombinant AKT1 protein as a kinase. Results showed that AKT1 directly phosphorylated WDHD1 as determined by the kinase analysis using PAS antibody immunoblotting [80]. These findings present convincing evidence that WDHD1 functions as a downstream target of the PI3K/AKT pathway (Figure 5).…”

“…As the downstream target of the PI3K/AKT pathway The occurrence and survival of tumors [80] As a cell cycle regulator and a downstream molecule in the PI3K/AKT pathway The occurrence and survival of tumors [19] Weighted gene co-expression network analysis As a hub gene [81] Lung adenocarcinoma…”

“…The identification of WDHD1 as a central gene linked to esophageal squamous cell carcinoma (ESCC) highlights its crucial involvement in the onset of esophageal cancer [19,81]. Significantly, WDHD1 acts as a target downstream of the PI3K/AKT pathway [80], playing a significant role in the progression of esophageal cancer by participating in abnormal cellular regulation through multiple downstream targets of AKT.…”

Formaldehyde-induced toxicity causes senescence and apoptosis in BMSCs via PI3K/P53 signaling pathways

“…Therefore, we reviewed senescence and apoptosis pathways and found that PIK3CA was a gene that co-regulated senescence and apoptosis pathways. PIK3CA encodes the p110a catalytic subunit of PI3K, which is responsible for the transformation of PI(4,5)P2 to the second messenger PI(3,4,5)P3, thus activating the PI3K signaling pathway and triggering a series of intracellular signal transmission, including cell cycle, apoptosis, P53 pathway, etc [31][32][33]. P53 is an important factor in the downstream of PI3K signaling pathway.…”