Integrative bioinformatics and experimental analysis revealed TEAD as novel prognostic target for hepatocellular carcinoma and its roles in ferroptosis regulation

Abstract

Objective: Transcriptional enhanced associate domain (TEAD) family consists of four members TEAD1/2/3/4 that regulate cell growth, stem cell functions and organ development. As the downstream of Hippo signaling pathway, TEAD family is involved in the progression of several cancers. However, the precise biology functions of TEAD family in hepatocellular carcinoma (HCC) have not been reported yet. Methods: We apply bioinformatics analysis based on databases including UALCAN, Oncomine, GEPIA, Kaplan-Meier plotter, WebGestalt, cBioPortal, TIMER2.0, and in vitro experimental evidence to identify the exact roles of TEAD family in HCC. Results: The results indicated that TEAD2/4 were significantly upregulated in HCC compared with normal tissues. Downregulated of TEAD2 could promote the death of HCC cells through inducing ferroptosis by iron accumulation and subsequent oxidative damage. According to the Kaplan-Meier plotter database, we found that the high expression of TEAD2 was significantly associated with poor disease-specific survival, overall survival, progression-free survival and relapse-free survival. In aspect of cancer immunity, Tumor Immune Estimation Resource algorithm showed that the expression of TEAD family members was obviously related to multiple of infiltrating immune cells including macrophages, neutrophils, dendritic cells, B cells, CD8+ T cells and CD4+ T cells. Finally, we conducted the functional enrichment analysis including protein-protein interaction

Role of hippo pathway and cuproptosis-related genes in immune infiltration and prognosis of skin cutaneous melanoma

“…Melanoma is more likely to occur in individuals who express high levels of FDX1; hence, this gene could serve as a prognostic marker for patients with melanoma. At present, some studies suggested that the Hippo pathway might have relationship with ferroptosis in cancer ( Ren et al, 2022 ). Currently, no studies have demonstrated the regulatory role of the Hippo pathway in cuproptosis.…”

Role of ferroptosis and its non-coding RNA regulation in hepatocellular carcinoma

“…It is showed that PRDX1 (peroxiredoxin 1), a ferroptosis promoter, combines with GPX2, MT3 (membrane receptor 3) and SRXN1 (sulfiredoxin 1) to establish an effective prognosis model for HCC ( Luo et al, 2022 ). In addition, TEAD2 (TEA domain transcription factor 2), a ferroptosis regulator, is demonstrated to function as novel prognostic target for the prediction of HCC outcome, and is associated with infiltrating immune cells including macrophages, neutrophils, and lymphocytes ( Ren et al, 2022 ). Furthermore, increasing ferroptosis-related gene signature has been proved to predict HCC survival and treatment.…”

Ferroptosis: From Basic Research to Clinical Therapeutics in Hepatocellular Carcinoma

“…Table 2 summarizes some molecular targets of ferroptosis in HCC. 15,17,27,28,42,[47][48][49][50][51][53][54][55][56]59,[61][62][63][64][65][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85] Figure 2 shows the regulatory pathways and some of the targets of ferroptosis in HCC.…”

“…55 Integrative bioinformatics and experimental analysis revealed that TEAD can serve as a novel prognostic target for HCC, and that knockdown of TEAD2 induces ferroptosis through iron accumulation and subsequent oxidative damage. 73 P53, a tumor suppressor implicated in the cell cycle, apoptosis, and cell senescence, has been reported to promote ferroptosis by inhibiting SLC7A11 expression and cystine uptake, 74 whereas mutant p53 has been shown to inhibit the ferroptotic capacity of cells. 86 Furthermore, zinc finger protein 498 inhibits the transcriptional activity of p53 by interfering with p53 Ser46 phosphorylation, thereby inhibiting apoptosis and ferroptosis in HCC cells.…”