Transcriptional Regulation of Aldehyde Dehydrogenase 1A1 Gene by Alternative Spliced Forms of Nuclear Factor Y in Tumorigenic Population of Endometrial Adenocarcinoma

Abstract

High activity of aldehyde dehydrogenase (ALDH) is characteristic of normal and cancerous stem cells. Recently, high ALDH expression was shown to be associated with poor prognosis in uterine endometrial adenocarcinoma. The population with high ALDH activity (ALDH-hi) was more invasive, anti-apoptotic, and tumorigenic than that with low activity (ALDH-lo). Here, the transcriptional regulation of ALDH1A1 gene, which is responsible for ALDH activity, was examined in endometrial adenocarcinoma. The promoter region of ALDH1A1 contained CCAAT and octamer binding motifs, and their mutation diminished promoter activity. Among CCAAT-recognizing transcription factors, nuclear factor YA (NFYA) was involved in ALDH1A1 transcription. Two alternatively spliced isoforms of NFYA (NFYA-long and NFYA-short) have been reported. The sorted ALDH-hi population of endometrial adenocarcinoma preferentially expressed NFYA-short, whereas ALDH-lo dominantly expressed NFYA-long. NFYA-short possessed higher transactivation ability than did NFYA-long. In addition, an additive effect of NFYA with Oct-1, which recognizes octamer binding motif, was observed in ALDH1A1 transactivation. These results indicate that the alternatively spliced isoforms of NFYA, in cooperation with Oct-1, play an important role in ALDH1A1 expression in endometrial adenocarcinoma.

Clinical translation for endometrial cancer stem cells hypothesis

“…ALDH has a promotor region CCAAT which is recognizes the transcription factor nuclear factor YA (NFYA). It has been proved that NFYA has a role in the stem properties induced by ALDH [77]. As previously mentioned, the expression of Musashi was equal considering ALDH-positive and ALDH-negative cells on endometrial cancer cells, what points this marker not exclusive of tumor initiating cells [55].…”

“…ALDH oxidizes intracellular aldehydes to carboxylic acids contributing to the synthesis of retinoic acid and neurotransmitter γ-amino butyric acid (GABA) in the early stage of stem cell differentiation. ALDH high -expression was associated with poor prognosis in endometrial cancers [77]. ALDH-1 high expression cells were more tumorigenic, resistant to chemotherapy agents and more invasive than ALDH low .…”

Cadherins Associate with Distinct Stem Cell-Related Transcription Factors to Coordinate the Maintenance of Stemness in Triple-Negative Breast Cancer

“…Interestingly, CDH2/4/6/17-enriched genes including two SC-TFs (MCM2 and FOXM1) were mainly grouped into a cluster that can be regulated by Nuclear Transcription Factor Y (NFY) and/or MECOM (EVI1) (Table 3), both of which have been reported to be involved in stem cell regulation [41, 42]. Therefore, our findings suggested that NFYs and MECOM might be the master transcription factors responsible for gene regulation and stem cell maintenance under the alterations of CDH2/4/6/17.…”

Associations between RNA splicing regulatory variants of stemness‐related genes and racial disparities in susceptibility to prostate cancer

“…Aldehyde dehydrogenase serves as a binding protein for metabolic molecules and potentially functions as an antioxidant, which links it to a role in maintaining stemness . In particular, one study has shown that ALDH1A1(+) prostate cancer cells exhibit high clonogenic and tumorigenic capacities . Isoforms of ALDH1A1 , generated by alternative RNA splicing, are associated with different expression levels of the gene in endometrial adenocarcinoma patients .…”

“…38 In particular, one study has shown that ALDH1A1(1) prostate cancer cells exhibit high clonogenic and tumorigenic capacities. 39 Isoforms of ALDH1A1, generated by alternative RNA splicing, are associated with different expression levels of the gene in endometrial adenocarcinoma patients. 39 In this study, one SNP in the ALDH1A1 exon region, which is predicted to affect alternative RNA splicing, is in LD with the identified SNP associated with prostate cancer risk in African population.…”