Positive feedback loop and synergistic effects between hypoxia‐inducible factor‐2α and stearoyl–CoA desaturase‐1 promote tumorigenesis in clear cell renal cell carcinoma

Abstract

Adapting to hypoxic stress is pivotal in tumor progression and determining tumor malignancy. The transcriptional factor hypoxia-inducible factor (HIF) is crucial in modulating tumorous hypoxic responses through altering cell energy metabolism, which includes the modification of glucose and lipid metabolism-associated gene expression. Stearoyl-CoA desaturase-1 (SCD1) is the main isoform of SCDs, the rate-limiting enzymes in the biosynthesis of monounsaturated fatty acids from saturated fatty acids, which is extensively activated in cancer progression. In this study, we found that SCD1 and HIF-2a were overexpressed in human clear cell renal cell carcinoma (ccRCC) tissues and ccRCC cell lines, and were upregulated in the 786-0 ccRCC cell line under hypoxia. Knockdown of SCD1 or HIF-2a impacted the other's expression. Enhancing SCD1 resulted in HIF-2a upregulation, which could be blocked by inhibiting the PI3K ⁄ Akt pathway. Deficiency of SCD1 or HIF-2a in 768-0 cells led to apoptosis, less colony formation ability, and decreased cell migration. More obvious effects were observed in 786-0 cells with double SCD1 and HIF-2a knockdown. These results indicate a PI3K ⁄ Akt-mediated loop between SCD1 and HIF-2a that mutually enhances their protein levels. Both SCD1 and HIF-2a are critical to promoting tumorigenesis by synergistically acting on maintaining cell survival, triggering cell migration, and enhancing the colony formation ability of cancer cells. (Cancer Sci 2013; 104: 416-422) T he von Hippel-Lindau (VHL) protein is a tumor suppression protein whose function is to mediate HIFa degradation and whose gene mutation is commonly found in human ccRCCs.(1) Aberrations in VHL's functions lead to HIFa accumulation irrespective of hydroxylation and upregulation of a series of hypoxia responsive genes in ccRCC.(2) Hypoxiainducible factor is a key transcriptional factor mediating cellular adaptation to hypoxic stress in carcinoma cells. It is an a ⁄ b heterodimeric DNA binding complex that is regulated through stabilization, dissociation, and degradation of subunit HIFa under normoxia.(3) The two best characterized HIFa isoforms are HIF-1a and HIF-2a. Although most of their functions are overlapping, the two isoforms have distinct functions in tumor cells.(4) Moreover, there is an overexpression trend toward HIF-2a rather than HIF-1a in VHL-defective ccRCC cells, (5) which might be due to reciprocal suppression effects between the isoforms. Energy metabolism reprogram is a major consequence after HIFa overexpression. Based on unique activities of these HIFa isoforms, HIF-1a is thought to be primarily involved in glucose metabolism by increasing glucose transporter expression and glycolytic enzymes.(7) Many glucose metabolism-associated genes are regulated by HIF-1a but not HIF-2a.(7) The latter is supposed to participate in angiogenesis modulation, enhancing tumor growth, and triggering cell cycle progression.(6) In another important energy metabolism, lipid metabolism, the two HIFa isoforms showed opposing effects on mo...

High Expression of Stearoyl-CoA Desaturase 1 Predicts Poor Prognosis in Patients with Clear-Cell Renal Cell Carcinoma

“…Von Roemeling et al reported that SCD1 might be a novel molecular therapeutic target for clear cell renal cell carcinoma, for which increased SCD1 expression was observed in ccRCC and it was essentially associated with ccRCC viability[19]. As showed in our previous study, there might be positive feedback loop and synergistic effects between SCD1 and hypoxia-inducible factor-2α (HIF-2α), which suggested that SCD1 might have a cross-talk with HIF in ccRCC[20]. Anyway, further studies need to be carried out in ccRCC to decipher the mechanism of aberrant SCD1 upregulation.…”

“…As described in detail previously, SCD1 was overexpressed in human ccRCC tissues and ccRCC cell lines. It had also showed that knockdown of SCD1 gene expression in 786-O human ccRCC cells led to tumor cells apoptosis, significantly delays the formation of tumors, and reduces the growth rate of tumors formed[20]. However, the exact correlation between protein level and clinical significance of SCD1 expression in ccRCC patients still remains unclear.…”

Hypoxia induces a lipogenic cancer cell phenotype via HIF1α-dependent and -independent pathways

“…Saturated FAs can be metabolized to MUFAs by SCD-1, a key regulator of this process. SCD-1 is an O 2 -dependent enzyme specific for palmitate and stearate, adding a double bond nearly always in “ cis ”- Δ9 and thereby forming palmitoleate or oleate, respectively [ 48 - 50 ]. SCD-1 was found to be constitutively expressed in several human cancers [ 48 , 51 , 52 ].…”

Roles of fatty acid metabolism in tumourigenesis: Beyond providing nutrition (Review)

“…In addition, the synergistic effect of hypoxia and FA metabolism has been verified. Zhang et al (84) reported that the PI3K/Akt-mediated crosstalk between SCD1 and HIF-2α contributes to cancer progression. Therefore, the promotion of metabolic changes in FAs under hypoxic conditions may be an area of interest for future investigations into cancer development.…”