ALDH1A3, a metabolic target for cancer diagnosis and therapy

Duan, Jiang‐Jie; Cai, Jingyi; Guo, Yufeng; Bian, Xiu‐Wu; Yu, Shanshan

doi:10.1002/ijc.30091

Cited by 99 publications

(104 citation statements)

References 90 publications

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“…Among the 87 genes identified in the array (Figure 4—figure supplement 3B; Figure 4-source data file 2), we focused on Aldh1a3 for its potential relevance in NPCs. Indeed, ALDH1A3 was shown to support self-renewal and clonogenic potential of cancer stem cells (Duan et al, 2016), including glioma stem cells (Mao et al, 2013), which can differentiate into neurons and glial cells like NPCs (Lathia et al, 2015). …”

Section: Resultsmentioning

confidence: 99%

“…Among these targets, we focused on ALDH1A3, a metabolic enzyme that was identified as marker of cancer stem cells. Since ALDH1A3 supports the clonogenic and tumorigenic potential of cancer stem cells (Duan et al, 2016; Mao et al, 2013), we hypothesized that it might also promote stemness in NPCs and that Sam68 exerted its effects through modulation of ALDH1A3 expression. Indeed, Khdrbs1 -/- NPCs displayed lower ALDH enzymatic activity and ALDH1A3 protein expression.…”

Section: Discussionmentioning

confidence: 99%

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Sam68 promotes self-renewal and glycolytic metabolism in mouse neural progenitor cells by modulating Aldh1a3 pre-mRNA 3'-end processing

Rosa

Bielli

Compagnucci

et al. 2016

eLife

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The balance between self-renewal and differentiation of neural progenitor cells (NPCs) dictates neurogenesis and proper brain development. We found that the RNA- binding protein Sam68 (Khdrbs1) is strongly expressed in neurogenic areas of the neocortex and supports the self-renewing potential of mouse NPCs. Knockout of Khdrbs1 constricted the pool of proliferating NPCs by accelerating their cell cycle exit and differentiation into post-mitotic neurons. Sam68 function was linked to regulation of Aldh1a3 pre-mRNA 3'-end processing. Binding of Sam68 to an intronic polyadenylation site prevents its recognition and premature transcript termination, favoring expression of a functional enzyme. The lower ALDH1A3 expression and activity in Khdrbs1-/- NPCs results in reduced glycolysis and clonogenicity, thus depleting the embryonic NPC pool and limiting cortical expansion. Our study identifies Sam68 as a key regulator of NPC self-renewal and establishes a novel link between modulation of ALDH1A3 expression and maintenance of high glycolytic metabolism in the developing cortex.DOI: http://dx.doi.org/10.7554/eLife.20750.001

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sam68 promotes self-renewal and glycolytic metabolism in mouse neural progenitor cells by modulating Aldh1a3 pre-mRNA 3'-end processing

Rosa

Bielli

Compagnucci

et al. 2016

eLife

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“…7 More details have been discussed elsewhere. 20 In order to address the therapeutic significance of ALDH1A3, we knocked out this gene and found the functional relevance with the cell cycle, which could lead to decreased proliferation, invasion both in vitro and in vivo. Combining all these evidence, it can be stated that ALDH1A3 could be potentially a target in the future to overcome the chemoresistance via intervening cell cycle mechanisms.…”

Section: Discussionmentioning

confidence: 99%

ALDH1A3 correlates with luminal phenotype in prostate cancer

et al. 2017

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Prostate cancer is the most common male malignancies in the United States. The specific characteristics of different disease stages have been deeply investigated. We present our data on ALDH1A3 as a potential therapeutic target for the prostate cancer based on several functional investigations. Also, we used The Cancer Genome Atlas datasets for primary prostate cancer to detect the relevance of ALDH1A3 and prostate cancer luminal phenotype. We found that ALDH1A3 correlated with androgen receptor signaling pathway in primary prostate cancer, which is consistent with its luminal layer localization. Then, from the genetic manipulation assay, we knocked out the ALDH1A3 in PC-3 cells and found significantly reduced proliferation rate as well as the invasion ability. Furthermore, we looked up our single center primary prostate cancer post-operative follow-up data and suggested that the high level ALDH1A3 expression could predict the poor progression-free survival in a 158-patient cohort. We concluded that ALDH1A3, localized in luminal layer in prostate epithelium, is highly expressed in prostate cancer. It played important role in maintaining the proliferation, invasion, and cell cycle. It can also become the potential biomarker in the future to guide the therapeutic manipulations for primary prostate cancer.

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“…Aldh1a3 is a detoxifying enzyme that catalyses the oxidation of retinal to retinol using NAD + . It is also involved in other metabolic processes including amino acid metabolism and the metabolism of lipid peroxidation products (Duan et al 2016). Therefore, its upregulation in the islets of diabetic animals and T2D subjects could be a response to oxidative stress and the ensuing damage.…”

Section: Journal Of Endocrinologymentioning

confidence: 99%

Mechanisms of β-cell dedifferentiation in diabetes: recent findings and future research directions

Bensellam

Jonas

Laybutt

2018

Journal of Endocrinology

203

171

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Like all the cells of an organism, pancreatic β-cells originate from embryonic stem cells through a complex cellular process termed differentiation. Differentiation involves the coordinated and tightly controlled activation/repression of specific effectors and gene clusters in a time-dependent fashion thereby giving rise to particular morphological and functional cellular features. Interestingly, cellular differentiation is not a unidirectional process. Indeed, growing evidence suggests that under certain conditions, mature β-cells can lose, to various degrees, their differentiated phenotype and cellular identity and regress to a less differentiated or a precursor-like state. This concept is termed dedifferentiation and has been proposed, besides cell death, as a contributing factor to the loss of functional β-cell mass in diabetes. β-cell dedifferentiation involves: (1) the downregulation of β-cell-enriched genes, including key transcription factors, insulin, glucose metabolism genes, protein processing and secretory pathway genes; (2) the concomitant upregulation of genes suppressed or expressed at very low levels in normal β-cells, the β-cell forbidden genes; and (3) the likely upregulation of progenitor cell genes. These alterations lead to phenotypic reconfiguration of β-cells and ultimately defective insulin secretion. While the major role of glucotoxicity in β-cell dedifferentiation is well established, the precise mechanisms involved are still under investigation. This review highlights the identified molecular mechanisms implicated in β-cell dedifferentiation including oxidative stress, endoplasmic reticulum (ER) stress, inflammation and hypoxia. It discusses the role of Foxo1, Myc and inhibitor of differentiation proteins and underscores the emerging role of non-coding RNAs. Finally, it proposes a novel hypothesis of β-cell dedifferentiation as a potential adaptive mechanism to escape cell death under stress conditions.

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ALDH1A3, a metabolic target for cancer diagnosis and therapy

Cited by 99 publications

References 90 publications

Sam68 promotes self-renewal and glycolytic metabolism in mouse neural progenitor cells by modulating Aldh1a3 pre-mRNA 3'-end processing

Sam68 promotes self-renewal and glycolytic metabolism in mouse neural progenitor cells by modulating Aldh1a3 pre-mRNA 3'-end processing

ALDH1A3 correlates with luminal phenotype in prostate cancer

Mechanisms of β-cell dedifferentiation in diabetes: recent findings and future research directions

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