Selective DHCR7 inhibition versus AEBS modulation: Mechanistic implications for tamoxifen effects in AML

We read with great interest the article by Dai et al., ‘7-dehydrocholesterol reductase (DHCR7) drives AML development through the IL-6/JAK2/STAT3 signalling pathway’,1 which reports an oncogenic role for DHCR7 in acute myeloid leukaemia (AML) and proposes DHCR7 as a therapeutic target based in part on pharmacological inhibition using tamoxifen and 4-hydroxytamoxifen. Genetic knockdown data convincingly support a functional role for DHCR7 in AML cell proliferation, cholesterol homeostasis and downstream signalling. However, we would like to comment on the interpretation of the pharmacological experiments and the mechanistic conclusions derived from them. Tamoxifen and 4-hydroxytamoxifen are high-affinity ligands of the microsomal anti-oestrogen binding site (AEBS), a heterooligomeric complex composed of emopamil-binding protein (EBP; 3β-hydroxysteroid sterol Δ8–Δ7 isomerase) and DHCR7.2 Importantly, within this complex, DHCR7 does not function as the primary catalytic target of tamoxifen but rather modulates ligand affinity for AEBS, as demonstrated by Kedjouar et al.2 In contrast, EBP carries the catalytic activity of cholesterol-5,6-epoxide hydrolase (ChEH), which has been molecularly assigned to AEBS3 and reviewed extensively.4 Consequently, tamoxifen does not act as a selective inhibitor of DHCR7 enzymatic activity. AEBS modulation induces complex sterol reprogramming. In addition to stimulating cholesterol epoxidation and lipid peroxidation, AEBS inhibition leads to accumulation of bioactive 5,6-epoxycholestanols, which promote tumour cell differentiation and cell death.5, 6 In parallel, tamoxifen induces accumulation of zymostenol, whereas 4-hydroxytamoxifen preferentially induces accumulation of zymosterol.2 Notably, accumulation of these sterol intermediates has been associated with induction of a pro-survival autophagy response in cancer cells.7, 8 Thus, AEBS ligands can simultaneously engage sterol-dependent pathways leading to either cell death or adaptive survival, depending on the balance of downstream metabolites. This mechanism is distinct from bona fide DHCR7 inhibition. Studies by Porter, Korade and colleagues identified selective DHCR7 inhibitors that generate a characteristic sterol profile marked by accumulation of 7-dehydrocholesterol (7-DHC) and formation of 7-DHC–derived oxysterols via free-radical chemistry.9, 10 These biochemical consequences differ fundamentally from those induced by AEBS ligands such as tamoxifen. In the present study,1 only 7-DHC was measured following tamoxifen or 4-hydroxytamoxifen treatment, without analysis of other discriminating sterols such as zymosterol, zymostenol or 5,6-epoxycholestanols, nor assessment of ChEH activity. Without these analyses, the observed metabolic, signalling and anti-proliferative effects cannot be specifically attributed to DHCR7 inhibition rather than AEBS-mediated mechanisms (Figure S1). While phenotypic similarities between DHCR7 knockdown and tamoxifen treatment are intriguing, they do not demonstrate selective pharmacological inhibition of DHCR7. Conclusions regarding DHCR7 as a pharmacologically validated therapeutic target in AML should therefore be interpreted with caution, and genetic evidence for DHCR7 function should be clearly distinguished from the broader AEBS-dependent effects of tamoxifen. Marc Poirot, Philippe de Medina, Sandrine Silvente-Poirot: Conceptualization, writing—original draft and writing—review and editing. This work has not been funded. The authors have no conflicts of interest to disclose. Data sharing not applicable to this article as no datasets were generated or analysed during the current study. Figure S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.