The Expanding Role of Cancer Stem Cell Marker ALDH1A3 in Cancer and Beyond

Abstract

Aldehyde dehydrogenase 1A3 (ALDH1A3) is one of 19 ALDH enzymes expressed in humans, and it is critical in the production of hormone receptor ligand retinoic acid (RA). We review the role of ALDH1A3 in normal physiology, its identification as a cancer stem cell marker, and its modes of action in cancer and other diseases. ALDH1A3 is often over-expressed in cancer and promotes tumor growth, metastasis, and chemoresistance by altering gene expression, cell signaling pathways, and glycometabolism. The increased levels of ALDH1A3 in cancer occur due to genetic amplification, epigenetic modifications, post-transcriptional regulation, and post-translational modification. Finally, we review the potential of targeting ALDH1A3, with both general ALDH inhibitors and small molecules specifically designed to inhibit ALDH1A3 activity.

Keywords: ALDH1A3; cancer stem cells; cell signaling; chemoresistance; diabetes; gene expression; glycometabolism; inhibitors.

Figure 2

Mechanisms of regulation of ALDH1A3 in cancer. ALDH1A3 is transcriptionally regulated by (1) Yap-activated RAR-RXR [67], and (2) transcription factors CEBPβ [69], (3) FOXD1 [81]. ALDH1A3 is epigenetically regulated by (4) promoter DNA methylation [83] and (5) histone methylation by KDM4C [43]. (6) The ALDH1A3 gene is also amplified in some cancers, as summarized in Table 1. ALDH1A3 is post-transcriptionally regulated by non-coding RNAs via (7) circCYP24A1 [71], which sponges miR-1301-3p, preventing its binding and targeting of the ALDH1A3 mRNA, or by (8) miR-7, MIR600HG, and miR-487b-3p, which target the ALDH1A3 transcript through binding sequences in its 3′UTR [56,72,88]. ALDH is regulated post-translationally by (9) USP9X, which deubiquitinates ALDH1A3, inhibiting its degradation [82]. ALDH1A3 is regulated indirectly by other signaling pathways, such as (10) activation of EGFR, which leads to increased ALDH1A3 levels [79]. This figure was created with BioRender.com.

Figure 1

Cancer-promoting mechanisms of ALDH1A3. (1) ALDH1A3 can oxidize retinal to retinoic acid (RA) and [4] (2) RA induces gene expression changes by binding heterodimers of RAR and RXR, which are bound to RARE sequences in gene promoter regions [13]. RA-inducible genes include NRAD1 (LINC00284), TG2, MUC4. (3) ALDH1A3 also regulates the expression of many other genes through unknown mechanisms leading to cancer-promoting effects [40]. (4) ALDH1A3 regulates gene expression indirectly through NRAD1, an inducible gene by the ALDH1A3-RA pathway. NRAD1 binds chromatin leading to the regulation of genes enriched in biological processes that regulate catabolism and differentiation [77]. (5) Through ALDH1A3 the PI3K/AKT/mTOR signaling pathway becomes upregulated, which leads to a decrease in docetaxel sensitivity and [71] (6) PPARγ levels [52]. PPARγ forms a heterodimer with RXR and increases HK expression. HK increases glucose uptake, lactate production, and ATP production. (7) ALDH1A3-regulated NRAD1 can sponge miRNAs and therefore lead to gene expression changes [77]. (8) Through the ALDH1A3-RA pathway, tTG (encoded by TG2) binds to p110, p85, and c-Src to induce the AKT/mTORC1/p70 S6-kinase pathway and increases cell survival [78]. This figure was created with BioRender.com.