Pyruvate kinase M2 interacts with nuclear sterol regulatory element–binding protein 1a and thereby activates lipogenesis and cell proliferation in hepatocellular carcinoma

Abstract

Dysregulation of lipid metabolism is common in cancer cells, but the underlying mechanisms are poorly understood. Sterol regulatory elementbinding proteins (SREBPs) stimulate lipid biosynthesis through transcriptional activation of lipogenic enzymes. However, SREBPs' roles and potential interacting partners in cancer cells are not fully defined. Using a biochemical approach, we found here that pyruvate kinase M2 (PKM2) physically interacts with the nuclear form of SREBP-1a (nBP1a), by binding to amino acids 43-56 in nBP1a. We also found that PKM2 activates SREBP target gene expression and lipid biosynthesis by stabilizing nBP1a proteins. Using a competitive peptide inhibitor to block the formation of the SREBP-1a/PKM2 complex, we observed that this blockade inhibited lipogenic gene expression. Of note, nBP1a phosphorylation at Thr-59 enhanced the binding to PKM2 and promoted cancer cell growth. Moreover, we show that PKM2 phosphorylates Thr-59 in vitro. Lastly, in human patients with hepatocellular carcinoma, nBP1a phosphorylation at Thr-59 was negatively correlated with clinical outcomes. Together, our results reveal that nBP1a/PKM2 interaction activates lipid metabolism genes in cancer cells and that Thr-59 phosphorylation of SREBP-1a plays an important role in cancer cell proliferation.Lipids are essential for cell proliferation. In fact, it has been estimated that more than 90% fatty acids in tumors cells are derived from de novo biosynthesis, while normal cells obtain lipids primarily from the circulation (1). In several types of cancer, including breast and prostate cancer, fatty acid synthase (Fasn) gene is up regulated (2), suggesting that fatty acid biosynthesis may play a role in cancer pathogenesis. Sterol regulatory element-binding proteins (SREBPs) are conserved transcription factors that can activate the transcription of genes encoding the key lipogenic enzymes, including Fasn (3,4). In mammalian cells, there are three SREBP isoforms (SREBP-1a, -1c and -2) encoded by two different genes, Srebf1 and Srebf2 (5). Two distinct promoters generate SREBP1a and SREBP-1c isoforms from the Srebf1 gene (5). Interestingly, Srebf1a is expressed at higher levels in cancer cells as compared to normal tissues, while Srebf1c is the predominant product of Srebf1 in normal tissues (6). In addition, SREBP-1a is a potent transcriptional activator for all known SREBP-target genes (7). The SREBP1 protein levels are often correlated with tumor size, histological grade and metastasis, and SREBP1 loss of function inhibits cell proliferation and induces apoptosis, cell migration and invasion in liver, ovarian and endometrial cancers (8)(9)(10)(11). Furthermore, genetic depletion or pharmacological inhibition of SREBP1 has been shown to suppress the epidermal growth factor receptor (EGFR)-induced glioblastoma (12). Blocking SREBP pathway prevents hepatocellular carcinoma (HCC) in mouse models (13). Thus, SREBP1 is required to support proliferation in some cancer cells.Previous studies have shown that pyruvate kinase isoform M...

Down‐regulation of PKM2 decreases FASN expression in bladder cancer cells through AKT/mTOR/SREBP‐1c axis

“…The previous study reported that PKM2 interacts with nuclear sterol regulatory element-binding protein 1a and thereby activates lipogenesis and cell proliferation in hepatocellular carcinoma (Zhao et al, 2018). Sterol regulatory element-binding protein-1a (SREBP-1a), SREBP-1c, and SREBP-2 are members of the SREBP family of transcription factors.…”

New links between lipid accumulation and cancer progression

“…Zhao et al (9) further show that PKM2-nBP1a complex formation results in increased nBP1a stability and Thr-59 phosphorylation. By using an nBP1a mutant (T59A) lacking the ability to be phosphorylated, they demonstrated the importance and fundamental nature of nBP1a Thr-59 phosphorylation by recapitulating these results in lung, colorectal, and breast cancer cell lines.…”

“…Thus, Zhao et al (9) have clearly shown that PKM2-nBP1a complex formation and subsequent Thr-59 phosphorylation stimulates nBP1a-dependent transcription and lipid accumulation, which are critical events necessary for cell proliferation and tumorigenesis (Fig. 1).…”

“…Using elegant biochemical and xenograft murine models, Zhao et al (9) have made the important discovery that a pyruvate kinase M2 (PKM2) activates nuclear SREBP-1a (nBP1a)dependent transcription, leading to cell proliferation and increased tumor progression. Regulation is initiated through the direct interaction of PKM2 with nBP1a through a PKM2binding motif.…”

Berberine Suppressed Tumor Growth through Regulating Fatty Acid Metabolism and Triggering Cell Apoptosis via Targeting FABPs

“…Lipids not only function as second messengers to transduce signals within cells but also serve as important energy sources when nutrients are limited [3]. Accumulating experiments have demonstrated that lipid metabolism is substantially reprogrammed in cancers [4][5][6]. e obvious feature of lipid metabolism in cancers is an increased rate of lipogenesis and mitochondrial fatty acid β-oxidation.…”