Aldehyde Dehydrogenases: Not Just Markers, but Functional Regulators of Stem Cells

Figure 2

Model of ALDH1A1 regulation, potential retinoid signaling pathways, and functional effects of ALDH in CSCs. Retinol is oxidized to retinal by retinol dehydrogenases, and retinal is then oxidized to RA by ALDH1 enzymes (green dotted line). In the classic pathway, RA enters the nucleus and binds to dimers of RARα and RXRs triggering the expression of its downstream target genes including RARβ (yellow dotted line). In the nonclassic pathway, RA binds to dimers of RXRs and PPARβ/δ to induce the expression of its downstream target genes including Akt (orange dotted line). In cells expressing ERα, RA can bind to dimers of RXRs and ERα (not shown). RA can also bind with RARα outside the nucleus to activate the PI3K/Akt pathway. Wnt pathway regulates ALDH1A1 through β-catenin/TCF-dependent transcription. MUC1-C induces ERK signaling and phosphorylates C/EBPβ. The complex of MUC1-C and C/EBPβ occupies the sequence upstream from the transcription initiation site of ALDH1, triggering ALDH1A1 expression. TGF-β-induced Smad4 downregulates ALDH1 (red dotted line). Notch promotes ALDH activity in CSCs through induction of deacetylase SIRT2, leading to ALDH1A1 deacetylation, while ALDH1A1 acetylation by acetyltransferase PCAF inhibits ALDH activity (blue dotted line; some parts of this figure were adapted with modifications from Figures 1 and 2 from Xu et al. [20], with editor’s permission).