A Feedback Circuitry between Polycomb Signaling and Fructose-1, 6-Bisphosphatase Enables Hepatic and Renal Tumorigenesis

Abstract

Suppression of gluconeogenesis elevates glycolysis and is commonly observed in tumors derived from gluconeogenic tissues including liver and kidney, yet the definitive regulatory mechanism remains elusive. Here, we screened an array of transcription regulators and identified the enhancer of zeste homolog 2 (EZH2) as a key factor that inhibits gluconeogenesis in cancer cells. Specifically, EZH2 repressed the expression of a rate-limiting gluconeogenic enzyme fructose-1, 6-bisphosphatase 1 (FBP1) and promoted tumor growth primarily through FBP1 suppression. Furthermore, EZH2 was upregulated by genotoxins that commonly induce hepatic and renal tumorigenesis. Genotoxin treatments augmented EZH2 acetylation, leading to reduced association between EZH2 and its E3 ubiquitin ligase SMURF2. Consequently, EZH2 became less ubiquitinated and more stabilized, promoting FBP1 attenuation and tumor formation. Intrigu-ingly, FBP1 physically interacted with EZH2, competed for EZH2 binding, and dissembled the polycomb complex. Therefore, FBP1 suppresses polycomb-initiated transcriptional responses and constitutes a double-negative feedback loop indispensable for EZH2-promoted tumorigenesis. Finally, EZH2 and FBP1 levels were inversely correlated in tumor tissues and accurately predicted patient survival. This work reveals an unexpected cross-talk between epigenetic and metabolic events, and identifies a new feedback circuitry that highlights EZH2 inhibitors as liver and kidney cancer therapeutics.Significance: A novel feedback loop involving EZH2 and suppression of the gluconeogenesis enzyme FBP1 promotes hepatocellular cancer growth.See related commentary by Leithner, p. 657

Epigenetic Marks Repressing Gluconeogenesis in Liver and Kidney Cancer

“…Enhancement of FBP1 expression could be exploited as a putative therapeutic approach to inhibit glycolysis and reverse the Warburg phenotype in cancer cells. In this study, the authors identified EZH2 as a negative regulator of FBP1 expression in liver and kidney cancer cells (1). A direct inhibitory effect of EZH2 on FBP1 expression via H3K27me3 in FBP1 promoter regions was shown in malignant liver and kidney epithelial cells using gain-of-function and loss-of-function experiments (1).…”

“…3,4). This article adds an important piece to the puzzle of deregulated cancer cell metabolism by dissecting a doublenegative feedback mechanism, leading to suppressed FBP1 expression in gluconeogenic tissues and enhancement of tumor growth (1).…”

<p>Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect</p>

“…The first loop is FBP1 and enhancer of zeste homolog 2 (EZH2): EZH2 can inhibit FBP1 and FBP1 physically competed for EZH2 binding in turn. 15 The second loop is FBP1 and polycomb repressive complex 2 (PRC2). PCR2 can downregulate FBP1, and conversely, FBP1 can interfere with PCR2 functions.…”

“…Nevertheless, the decrease of PCK1 and FBP1 expression in HCC compared to normal liver tissue lead to the suppression of gluconeogenesis and elevation of glycolysis. 15,16 As an emerging hallmark of tumors, studies regarding glucose metabolism reprogramming used to focus on glycolysis. However, the correlation between gluconeogenesis and tumors is rarely reported but may provide insight for the treatment of HCC.…”

Fructose-1, 6-bisphosphatase 1 interacts with NF-κB p65 to regulate breast tumorigenesis via PIM2 induced phosphorylation

“…Fructose-1, 6-biphosphatase 1 (FBP1) is a rate-limiting enzyme in gluconeogenesis, and functions as a negative regulator of the Warburg effect 1 . As a tumor suppressor, FBP1 plays a crucial role in tumor progression in multiple cancers 2 . Low expression of FBP1 is associated with tumorigenesis and poor prognosis in patients with breast, kidney, colon, pancreas, lung, stomach and liver cancers 3 - 8 .…”