HIF1/2α mediates hypoxia-induced LDHA expression in human pancreatic cancer cells

Abstract

Glycolysis is a typical conduit for energy metabolism in pancreatic cancer (PC) due to the hypoxic microenviroment. Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate and is considered to be a key checkpoint of anaerobic glycolysis. The aim of the present study was to explore the mechanism of interactions between hypoxia, HIF-1/2α and LDHA, and the function of LDHA on PC cells by analyzing 244 PC and paratumor specimens. It was found that LDHA was over-expressed and related to tumor stages. The result of in vitro study demonstrated that hypoxia induced LDHA expression. To explore the relationship between HIF and LDHA, chromatin immunoprecipitation assay and luciferase assay were performed. The result showed that HIF-1/2α bound to LDHA at 89bp under the hypoxic condition. Furthermore, knockdown of endogenous HIF-1α and HIF-2α decreased the LDHA expression even in the hypoxic condition, which was accompanied with a significant decrease in lactate production and glucose utilization (p < 0.01). Immunofluorescence in the 244 specimens showed that HIF-1/2α was over-expressed and associated with LDHA over-expression (p < 0.0001). Forced expression of LDHA promoted the growth and migration of PC cells, while knocking down the expression of LDHA inhibited the cell growth and migration markedly. In summary, the present study proved that HIF1/2α could activate LDHA expression in human PC cells, and high expression of LDHA promoted the growth and migration of PC cells.

Prognostic Value of Lactate Dehydrogenase Expression in Different Cancers: A Meta-Analysis

“…For instance, the hypoxia-inducible factor (HIF) helps cancer cells adapt to hypoxia microenvironments. 20 LDHA expression is commonly in direct proportion to the HIF-1 expression level. HIF-1 activates the expression of the LDHA gene by binding to hypoxia response elements.…”

Hypoxia-inducible factor (HIF)-prolyl hydroxylase 3 (PHD3) maintains high HIF2A mRNA levels in clear cell renal cell carcinoma

“…However, whereas RCC4 expresses both HIF-1␣ and HIF-2␣, 786-O expresses a truncated form of HIF1A transcript and thus lacks a functional HIF-1␣ protein but expresses a high basal level of HIF-2␣ (31,32). HIF-2␣ has previously been shown to transcriptionally regulate LDHA and GLUT1 (31,33,34). GLUT1 and LDHA expression responded similarly to PHD3 silencing in both cell lines suggesting that the responsible isoform may be HIF-2␣.…”

Cavefish cope with environmental hypoxia by developing more erythrocytes and overexpression of hypoxia inducible genes

“…To compare the molecular responses of surface fish and cavefish to the emulated hypoxic environment described above, qPCR analyses were performed using marker genes for hypoxia and hypoxia-related metabolic changes. We examined hif1al , a homologue of zebrafish hif3a that is transcriptionally regulated by the HIF1 hypoxia master regulator (Pasanen et al, 2010), and other genes controlled by HIF1 (Iyer et al, 1998, Kim et al, 2006, Cui et al, 2017): hexokinase 1 ( hk1 ), which is involved in glycolysis, lactate dehydrogenase a ( ldha ), which is involved in fermentation, and pyruvate dehydrogenase kinase1 ( pdk1 ), which is involved in inhibiting the TCA cycle in mitochondria. In addition, genes were assayed that are functionally associated with hypoxia or hypoxia induced processes, but not known to be controlled by HIF1: ATP-dependent 6-phosphofructokinase ( pfkma ), which is involved in glycolysis (Ptashne et al, 1983), lactate dehydrogenase b ( ldhb ) and monocarboxylate transporter1 ( mct1 ), which are involved in fermentation (Ždralević et al, 2018; Miranda-Gonçalves, 2016), and pyruvate dehydrogenase kinase 2 ( pdk2 ), which functions similarly to pdk1 but is regulated by hormones and insulin signaling pathways (Jeong et al, 2012).…”