Feedback Loop Regulation of SCAP/SREBP-1 by miR-29 Modulates EGFR Signaling-Driven Glioblastoma Growth

Abstract

Summary Dysregulated lipid metabolism is a characteristic of malignancies. Sterol regulatory element-binding protein-1 (SREBP-1), a transcription factor playing a central role in lipid metabolism, is highly activated in malignancies. Here, we unraveled a previously unappreciated link between miR-29 and the SCAP/SREBP-1 pathway in glioblastoma (GBM) growth. EGFR signaling enhances miR-29 expression in GBM cells via upregulation of SCAP/SREBP-1, and SREBP-1 activates miR-29 expression via binding to specific sites in its promoter. In turn, miR-29 inhibits SCAP and SREBP-1 expression by interacting with their 3′-untranslated regions. miR-29 transfection suppressed lipid synthesis and GBM cell growth, which were rescued by addition of fatty acids or N-terminal SREBP-1 expression. Xenograft studies showed that miR-29 mimics significantly inhibit GBM growth and prolong the survival of GBM-bearing mice. Our study reveals a previously unrecognized negative feedback loop in SCAP/SREBP-1 signaling mediated by miR-29, and suggests that miR-29 treatment may represent an effective means to target GBM.

SCAP/SREBPs are Central Players in Lipid Metabolism and Novel Metabolic Targets in Cancer Therapy

“…Accumulating evidence has shown that SCAP/SREBPs play important roles in malignancies, connecting oncogenic signaling to lipid metabolism alterations, leading to rapid tumor growth (Figure 1) [13, 60, 61, 76–78, 80, 82]. Multiple studies have suggested that SCAP/SREBPs are very promising molecular targets in cancer treatment.…”

“…We found that GBM tumors bearing amplified EGFR, or expressing EGFRvIII, the constitutively active form of the receptor that lacks a portion of the extracellular ligand-binding domain, were greatly dependent on SREBP-1-mediated lipid synthesis and uptake for rapid growth [61]. EGFR/EGFRvIII activates SREBP-1 through upregulation of PI3K/Akt signaling, promoting the expression of ATP citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), stearoyl-coenzyme A desaturase 1 (SCD1) and low density lipoprotein receptor (LDLR) to enhance fatty acid synthesis and cholesterol uptake [13, 60, 61, 80, 83]. …”

“…We recently reported that miR-29 mediates a novel negative feedback loop that regulates the SCAP/SREBP-1 signaling pathway and lipid metabolism (Figure 1) [80–81]. The miRNA-29 family consists of three members, miR-29a, −29b and −29c, which share the same seed sequence [97, 98].…”

“…The miRNA-29 family consists of three members, miR-29a, −29b and −29c, which share the same seed sequence [97, 98]. Analyzing a large cohort of tumor tissues from GBM patients with altered EGFR (amplification or mutation), we found that expression of all three mature miR-29s is positively correlated with SREBF1 gene expression [80, 81]. SREBP-1, via EGFR/PI3K/Akt signaling, transcriptionally upregulated the expression of all three miR-29s in GBM cells.…”

“…In turn, they could all bind to the 3’-UTR of SREBF1 and SCAP mRNAs, inversely inhibiting their expression. Importantly, administration of miR-29 mimics inhibited SCAP/SREBP-1 and significantly reduced GBM tumor growth [80, 81], suggesting that miR-29s could be used to target GBM.…”