MUC1: a novel metabolic master regulator

Abstract

MUC1, a type I transmembrane protein, is significantly overexpressed and aberrantly glycosylated in tumors of epithelial origin. By virtue of its aberrant signaling due to loss of apical-basal polarity in cancer, MUC1 regulates the metabolite flux at multiple levels. Serving as a transcriptional co-activator, MUC1 directly regulates expression of metabolic genes. By regulating receptor tyrosine kinase signaling, MUC1 facilitates production of biosynthetic intermediates required for cell growth. Also, via direct interactions, MUC1 modulates the activity/stability of enzymes and transcription factors that directly regulate metabolic functions. Additionally, by modulation of autophagy, levels of reactive oxygen species, and metabolite flux, MUC1 facilitates cancer cell survival under hypoxic and nutrient-deprived conditions. This article provides a comprehensive review of recent literature on novel metabolic functions of MUC1.

Keywords: Cancer metabolism; Glycolysis; MUC1; Nutrient stress and carbon flux.

Figure 1. Regulation of carbon flux by MUC1

MUC1 regulates glycolytic flux by activating multiple signaling pathways, such as PI3K/Akt/mTOR, p53, and HIF-1α that regulate transcription of glycolytic genes. Under glucose-deprived conditions, MUC1 activates AMPK that facilitates survival by inducing autophagy. The interaction of MUC1 with RTKs increases RTK membrane stability. Thus, the complex facilitates signaling downstream of RTK, which can modulate PKM2 activity transcriptional activation of glycolytic genes. Reciprocally, RTKs phosphorylate MUC1 and facilitate signaling downstream of MUC1. MUC1 also directly interacts with glycolytic enzymes like PKM2 to modulate the carbon flux. As a net result of the changes in gene expression and enzymatic activities, carbon flux to glycolysis is enhanced, whereas carbon flux to TCA cycle is decreased. MUC1-regulated genes/enzymes are indicated in blue. Abbreviations in the figure include the following: glucose transporter (GLUT), pentose phosphate pathway (PPP), phosphoglucomutase (PGM), pyruvate kinase isozyme M2 (PKM2), acetyl coenzyme A (AcCoA), pyruvate dehydrogenase (PDH), pyruvate dehydrogenase kinase 1 (PDK1), monocarboxylate transporter 1 (MCT1), 5′-adenosine monophosphate-activated protein kinase (AMPK), tuberous sclerosis (TSC), α-ketoglutarate (α-KG), solute carrier family 1 member 5 (SLC1A5), insulin-like growth factor 1 (IGF-1), receptor tyrosine kinase (RTK), phosphoinositide 3 kinase (PI3K), phosphatase and tensin homolog (PTEN), tricarboxylic acid cycle (TCA cycle), fatty acid (FA), mammalian target of rapamycin complex 1 (mTORC1) and electron transport chain (ETC).

Figure 2. MUC1 regulates HIF-1α activity and stability to regulate cancer metabolism

MUC1 modulates the overall metabolic flux to decrease the cellular levels of 2-ketoglutarate (2-KG), while increasing succinate levels. 2-KG is a substrate for prolyl hydroxylases (PHDs), whereas succinate is an inhibitor. PHDs cause proline hydroxylation of HIF-1α and mark it for proteasomal degradation. Hence, the net result of MUC1 expression is an increased stability of HIF-1α. MUC1 also facilitates transcriptional activity of HIF-1α by recruiting p300, a co-activator for HIF-1α, to the transcriptional complexes at glycolytic gene promoters in a hypoxia-dependent fashion. Abbreviations include the following: prolyl hydroxylase domain-containing protein (PHD), von Hippel-Lindau tumor suppressor (VHL), hypoxia inducible factor 1, alpha subunit (HIF-1α), Ubiquitin (Ub), glucose transporter1 (GLUT1), pentose phosphate pathway (PPP), and monocarboxylate transporter (MCT).

Figure 3. Regulation of ROS by MUC1

Signaling downstream of MUC1 regulates the expression levels of ROS-attenuating enzymes (SOD1/2, CAT, and GPx) and increases the flux through the pentose phosphate pathway (PPP) in order to fine tune ROS levels in cancer cells. The PPP pathway produces high levels of NADPH that can neutralize intracellular ROS. MUC1 also enhances expression of PDK1 and LDHA that cause decreased carbon flux to the TCA cycle and hence, decreased ROS production. Enzymes upregulated by MUC1 are indicated by an upward red arrow. All the enzymes are written in blue color. Metabolic pathways upregulated by MUC1 are indicated by an upward purple arrow, whereas a downward purple arrow indicates metabolic pathways downregulated by MUC1. Abbreviations include the following: glucose transporter1 (GLUT1), pentose phosphate pathway (PPP), glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), acetyl coenzyme A (AcCoA), MCT (Monocarboxylate transporter), TCA cycle (Tricarboxylic Acid cycle), pyruvate dehydrogenase (PDH), pyruvate Dehydrogenase Kinase 1 (PDK1), lactate dehydrogenase A (LDHA), α-Ketoglutarate (α-KG), and solute carrier family 1, member 5 (SLC1A5).