In accordance with these, Lee et al. resistant to HIF-2 antagonists in both wild-type (SLR21) ccRCC cell lines and patient-derived xenograft tumors with low level of HIF-2 [13,14]. In order to overcome the limited effects of HIF-2 antagonists, alternative therapeutic targets against ccRCC should be elucidated. Lee et al. [8] have identified a novel pathway of SREBP-1c-dependent ccRCC tumor, independent of mutation. First, they show that Alpl low level of RNF20 is significantly associated with poor prognosis in ccRCC patients, regardless of mutation status. Second, RNF20 represses SREBP-1c expression and cell growth in both wild-type (ACHN) and mutation. Therefore, they elucidate a novel pathway involved in a and co-operate to regulate cell proliferation and cell cycle [18,19]. In the recent study, Lee et al. [8] have found that SREBP-1c promotes Avatrombopag cell cycle progression by enhancing expression of and in a PTTG1-dependent manner, potentiating cell proliferation in ccRCC. Thus, SREBP-1cCPTTG1 axis provides new insights that SREBP-1c can directly regulate cell cycle in addition to controlling lipid metabolism through its well-known lipogenic targets. Avatrombopag Lipid availability is crucial for cell viability and cell cycle regulation. For instance, unsaturated fatty acids increase cyclin D1 expression and cell proliferation by activating -catenin in ccRCC [21]. In addition, the inhibitor of lipogenic enzyme SCD1 suppresses tumor growth and invasiveness of ccRCC [22]. Lee et al. also addressed the question whether lipogenesis is required for induction of PTTG1 and cell cycle genes [8]. They found that the expression of PTTG1 and cell cycle genes is not affected by pharmacological inhibition of lipogenesis using the ACC inhibitor TOFA or the FASN inhibitor C75 or by siRNA-mediated suppression of FASN. These results suggest that SREBP-1c separately regulates lipogenesis and PTTG1-mediated cell cycle progression. Taken together, the present work proposes that SREBP-1c serves as a molecular bridge between lipid metabolism and cell cycle regulation by modulating different pathways, which eventually coalesce to drive ccRCC tumorigenesis. Further insight into connection points between the lipid metabolism and cell cycle might pave the way for the development of effective therapies that target metabolic vulnerabilities of ccRCC. Another SREBP isoform, SREBP-2 plays a key role in tumor transformation and invasion through mevalonate pathway [23]. As described earlier, ccRCC is characterized by the accumulation of neutral lipids such as triglycerides and cholesterol esters. Previous studies have shown that the activity of esterification of cholesterol is significantly higher in ccRCC than in biosynthesis and uptake of cholesterol [24,25]. In accordance with these, Lee et al. [8] observed that the expression of SREBP-2 and cholesterol metabolism genes such as HMG-CoA reductase and LDL receptor appear to be decreased in ccRCC patients. While further studies on the effect of SREBP-2 on ccRCC tumorigenesis are needed, it is plausible to speculate that SREBP-1c will play more oncogenic roles in ccRCC. Figure 1 briefly summarizes the various signal transduction pathways involved in the regulation of SREBP-1c in ccRCC. Open in a separate window Figure 1 Regulation of SREBP-1c in ccRCC Future directions Many studies have reported that SREBP-1c is associated with cell cycle regulation. In recent paper, Lee et al. have identified a novel pathway by which SREBP-1c directly regulates the cell cycle through PTTG1 [8]. Moreover, they have proposed that SREBP-1c seems to regulate lipid metabolism and cell cycle pathways in a separate manner. Although Lee et al. revealed a novel mechanism of SREBP-1c-mediated cell cycle regulation, this study raises a number of important questions that require further investigation [8]. These experiments display that RNF20, a negative regulator of SREBP-1c, is definitely down-regulated in ccRCC. However, it is still unfamiliar how RNF20 manifestation is definitely down-regulated in ccRCC. Recently, it has been shown Avatrombopag that epigenetic rules of particular genes is definitely important during the tumorigenic [26,27] and metabolic processes [28]. For example, the RNF20 promoter consists of prominent CpG islands and is hypermethylated in human being breast tumor [6]. In addition, miRNAs have been shown to control the manifestation of tumor suppressors and oncogenes in various cancers [29]. Thus, it seems that RNF20 manifestation might be reduced by epigenetic modifications or miRNAs in ccRCC. On the other hand, this work shows the tumor-suppressive part of RNF20 in ccRCC.