Inactivation of 3-hydroxybutyrate dehydrogenase type 2 promotes proliferation and metastasis of nasopharyngeal carcinoma by iron retention

Abstract

BACKGROUND: 3-Hydroxybutyrate dehydrogenase type 2 (BDH2) is known to catalyse a rate-limiting step in the biogenesis of the mammalian siderophore and regulate intracellular iron metabolism. Here we aim to explore the expression and possible function of BDH2 in nasopharyngeal carcinoma (NPC). METHODS: The transcription and protein expression of BDH2 in NPC were determined by both real-time RT-PCR and immunohistochemistry staining assays. Cell proliferation, migration and invasion were evaluated by MTT assay, wound-healing assay and Transwell assay, respectively. The profile of genes regulated by restoring BDH2 expression in NPC cells was analysed by cDNA microarray. The level of iron in NPC cells was detected by iron colorimetric assay. RESULTS: The expression of BDH2 was significantly downregulated in NPC. Ectopic expression of BDH2 inhibited NPC cell proliferation and colony formation. Meanwhile, BDH2 suppressed the migration and invasion of NPC cells by reversing the epithelial-mesenchymal transition (EMT). In addition, a higher level of BDH2 decreased the growth and metastasis of NPC cells via reducing intracellular iron level. CONCLUSIONS: Our findings suggest that BDH2 may be a candidate tumour-suppressor gene in NPC. Decreasing intracellular iron could be an effective therapeutic approach for NPC.

Cross‑link between ferroptosis and nasopharyngeal carcinoma: New approach to radiotherapy sensitization (Review)

“…The conversion process between Fe 3+ and Fe 2+ is accompanied by the generation of energy, which benefits cellular energy metabolism ( 49 ). Similarly, it was demonstrated that reducing the level of intracellular iron via the tumor suppressor gene 3-hydroxybutyrate dehydrogenase type 2 inhibited the proliferation and metastasis of NPC cells ( 50 ). Furthermore, Xu et al ( 51 ) indicated that itraconazole was able to reduce the activity of NPC stem cells by increasing the concentration of intracellular iron in lysosomes and lipid peroxides.…”

Metabolic Reprogramming and Immune Evasion in Nasopharyngeal Carcinoma

“…Transferrin and transferrin receptors, which enable iron internalization from the extracellular environment, are necessary for ferroptosis (98,102). A low level of BDH2 (3-hydroxybutyrate dehydrogenase 2) amplifies NPC cell malignant behaviours by promoting intracellular iron overload, indicating that reduced intracellular iron might be favourable for NPC treatment (103). Fe is a S-adenosylmethionine (SAM) to provide methyl groups, and the formation of SAM depends on extracellular folic acid, which can be increased in NPC cells by a-folate receptor activity (108).…”

Development of cancer metabolism as a therapeutic target: new pathways, patient studies, stratification and combination therapy

“…Not all metabolic changes have to be increased to have a major effect on tumour biology. For example, it is shown in the study by Li et al 12 that low expression of 3-hydroxybutyrate dehydrogenase type 2 (BDH2) has a major effect on tumour iron metabolism in nasopharyngeal carcinoma. Apart from its effect on ketone body metabolism, BDH2 also affects intracellular iron concentrations, responds to iron and helps in the synthesis of a siderophore.…”