Comprehensive analyses of PDHA1 that serves as a predictive biomarker for immunotherapy response in cancer

Abstract

Recent studies have proposed that pyruvate dehydrogenase E1 component subunit alpha (PDHA1), a cuproptosis-key gene, is crucial to the glucose metabolism reprogram of tumor cells. However, the functional roles and regulated mechanisms of PDHA1 in multiple cancers are largely unknown. The Cancer Genome Atlas (TCGA), GEPIA2, and cBioPortal databases were utilized to elucidate the function of PDHA1 in 33 tumor types. We found that PDHA1 was aberrantly expressed in most cancer types. Lung adenocarcinoma (LUAD) patients with high PDHA1 levels were significantly correlated with poor prognosis of overall survival (OS) and first progression (FP). Kidney renal clear cell carcinoma (KIRC) patients with low PDHA1 levels displayed poor OS and disease-free survival (DFS). However, for stomach adenocarcinoma (STAD), the downregulated PDHA1 expression predicted a good prognosis in patients. Moreover, we evaluated the mutation diversity of PDHA1 in cancers and their association with prognosis. We also analyzed the protein phosphorylation and DNA methylation of PDHA1 in various tumors. The PDHA1 expression was negatively correlated with tumor-infiltrating immune cells, such as myeloid dendritic cells (DCs), B cells, and T cells in pan-cancers. Mechanically, we used single-cell sequencing to discover that the PDHA1 expression had a close link with several cancer-associated signaling pathways, such as DNA damage, cell invasion, and angiogenesis. At last, we conducted a co-expressed enrichment analysis and showed that aberrantly expressed PDHA1 participated in the regulation of mitochondrial signaling pathways, including oxidative phosphorylation, cellular respiration, and electron transfer activity. In summary, PDHA1 could be a prognostic and immune-associated biomarker in multiple cancers.

Insights into prognosis and immune infiltration of cuproptosis-related genes in breast cancer

“…Then, survival analysis was performed for the evaluation of prognostic role of the CRGs, and the result showed that the expression of PDHA1, LIPT1 and MTF1 were associated with the OS and RFS in BC, however, the COX analysis and T-stage associated survival analysis suggested only PDHA1 expression was significantly related to the prognosis of BC patients. Besides, previous studies have suggested that the expression of CRGs was closely associated with TME in various malignancies ( 37 , 40 ), and our study also found that FDX1, DLAT, PDHA1, GLS, CDKN2A were the highest expressed in C2, and LIPT1, LIAS, MTF1 were the highest expressed in C3. LIAS, DLD, DLAT and PDHB were negatively related to stromal score, immune score and estimate score, and FDX1, LIPT1 and GLS were positively related to three scores.…”

Cuproptosis: mechanisms and links with cancers

“…PDHA1 and PDHB form the α1 and β subunits of the PDC E1 component, respectively, and together form pyruvate dehydrogenase mediating pyruvate decarboxylation [ 125 ]. High levels of PDHA1 were thought to be associated with a better prognosis for lung cancer patients and can be used as a biomarker for the tumor microenvironment [ 108 ]. DLAT form the E2 component of PDC that acts as a dihydrolipoamide acetyltransferase catalyzing the biosynthesis of acetyl coenzyme A(acetyl-CoA) [ 107 ].…”

Integrative analysis revealed that distinct cuprotosis patterns reshaped tumor microenvironment and responses to immunotherapy of colorectal cancer

“…Similar to our previous results, the mRNA expressions of CDKN2A, GLS, and LIPT1 were upregulated in CRC, whereas the expressions of other CRGs were downregulated. As a crucial gene in the glucose metabolism reprogram of tumor cells, there is growing evidence that PDHA1 might act as a prognostic and immune-related biomarker and negatively associated with immune cell infiltration in TME ( 55 ). Western blotting confirmed that PDHA1 expression in normal colon cells was higher than that in CRC cells ( Figure 9K ).…”