ABAT and ALDH6A1, regulated by transcription factor HNF4A, suppress tumorigenic capability in clear cell renal cell carcinoma

Abstract

Background: Clear cell renal cell carcinoma (ccRCC) is a malignancy characterized by metabolic reprogramming. ABAT and ALDH6A1 are metabolic enzymes. In this study, we aim to investigate the associations of ABAT and ALDH6A1 with the malignancy of ccRCC cells. Methods: The gene expression levels of ABAT and ALDH6A1 in ccRCC were analyzed from gene expression microarray datasets and RNA sequencing data. Clinical information was analyzed from The Cancer Genome Atlas (TCGA) data. The distributions of ABAT and ALDH6A1 in ccRCC clinical tissues were screened by reverse transcription-quantitative polymerase chain reaction (RT-QPCR) and immunohistochemical assays. The effect of overexpression of ABAT or ALDH6A1 was measured by detecting the cell viability, migration ability, and the ratio of lactate and nicotinamide adenine dinucleotide phosphate (NADPH). Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were carried out to investigate the transcript regulation of HNF4A in ABAT and ALDH6A1. Results: Remarkable downregulated ABAT and ALDH6A1 expression levels were observed in ccRCC patients and low expression of ABAT and ALDH6A1 was correlated with poor survival. Overexpression of ABAT or ALDH6A1 significantly attenuated cell proliferation and migration, and impaired lactate production. In ABAT increased ccRCC cells, the ratio of NADPH/NADP+ was reduced. Finally, we demonstrated that ABAT and ALDH6A1 were directly regulated by a tumor suppressor, HNF4A. Conclusions: These observations identified HNF4A-regulated low-expressed ABAT and ALDH6A1 as promising diagnostic and prognostic biomarkers for ccRCC.

Identification of Hub Genes Associated With Hepatocellular Carcinoma Using Robust Rank Aggregation Combined With Weighted Gene Co-expression Network Analysis

“…Conversely, the downregulation of ABAT promotes the progression of BLBC ( Chen X. et al, 2019 ) and resistance to endocrine therapy of inflammatory breast cancer ( Jansen et al, 2015 ). Moreover, ABAT has been identified as a prognostic factor for renal cell carcinoma and hepatic adenocarcinoma ( Reis et al, 2015 ; Lu et al, 2020 ). Chen et al (2017) screened six genes related to HCC metastasis and prognosis through a co-expression network analysis, which led to the identification of DAO and ABAT.…”

Identification and validation of a two-gene metabolic signature for survival prediction in patients with kidney renal clear cell carcinoma

“…It has been previously reported that ALDH6A1 expression was markedly downregulated in KIRC tissues. Overexpression of ALDH6A1 signi cantly decreased cell proliferation and migration as well as impaired oncologic metabolism of KIRC [32]. Results from another study showed that hepatic neoplastic transformation seemed to inhibit the expression of ALDH6A1 through extensive quantitative proteomic pro ling analysis and molecular characterization [33].…”

“…ALDH6A1 expression was found to be markedly downregulated in KIRC tissues, in association with poor survival. Accordingly, its overexpression significantly decreased cell proliferation and migration and impaired oncologic metabolism in KIRC cells [ 29 ]. Results from another study employing extensive quantitative proteomic profiling analysis and molecular characterization suggested that hepatic neoplastic transformation inhibits the expression of ALDH6A1.…”

Controversial roles of hepatocyte nuclear receptor 4 α on tumorigenesis (Review)

“…Cyclin D1 was also demonstrated to directly bind to HNF4α and cause a decrease in downstream genes expression (61). Previous studies in renal cell carcinoma reported that decreased HNF4α expression is positively correlated with e-cadherin expression, suggesting a poor prognosis in patients (62)(63)(64). Furthermore, HNF4α expression is blocked by mutated IDH, which could promote biliary cancer progression (65).…”