MUC1 mucin stabilizes and activates hypoxia-inducible factor 1 alpha to regulate metabolism in pancreatic cancer.

Authors:
Nina V Chaika
Nina V Chaika
University of Nebraska Medical Center
United States
Teklab Gebregiworgis
Teklab Gebregiworgis
University of Nebraska-Lincoln
United States
Vinee Purohit
Vinee Purohit
University of Nebraska Medical Center
United States
Prakash Radhakrishnan
Prakash Radhakrishnan
University of Nebraska Medical Center
United States
Xiang Liu
Xiang Liu
Endoscopy Center
Tulsa | United States
Bo Zhang
Bo Zhang
The Second Affiliated Hospital of Dalian Medical University
Dalian Shi | China
Kamiya Mehla
Kamiya Mehla
University of Nebraska Medical Center
United States

Proc Natl Acad Sci U S A 2012 Aug 6;109(34):13787-92. Epub 2012 Aug 6.

Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Aberrant glucose metabolism is one of the hallmarks of cancer that facilitates cancer cell survival and proliferation. Here, we demonstrate that MUC1, a large, type I transmembrane protein that is overexpressed in several carcinomas including pancreatic adenocarcinoma, modulates cancer cell metabolism to facilitate growth properties of cancer cells. MUC1 occupies the promoter elements of multiple genes directly involved in glucose metabolism and regulates their expression. Furthermore, MUC1 expression enhances glycolytic activity in pancreatic cancer cells. We also demonstrate that MUC1 expression enhances in vivo glucose uptake and expression of genes involved in glucose uptake and metabolism in orthotopic implantation models of pancreatic cancer. The MUC1 cytoplasmic tail is known to activate multiple signaling pathways through its interactions with several transcription factors/coregulators at the promoter elements of various genes. Our results indicate that MUC1 acts as a modulator of the hypoxic response in pancreatic cancer cells by regulating the expression/stability and activity of hypoxia-inducible factor-1α (HIF-1α). MUC1 physically interacts with HIF-1α and p300 and stabilizes the former at the protein level. By using a ChIP assay, we demonstrate that MUC1 facilitates recruitment of HIF-1α and p300 on glycolytic gene promoters in a hypoxia-dependent manner. Also, by metabolomic studies, we demonstrate that MUC1 regulates multiple metabolite intermediates in the glucose and amino acid metabolic pathways. Thus, our studies indicate that MUC1 acts as a master regulator of the metabolic program and facilitates metabolic alterations in the hypoxic environments that help tumor cells survive and proliferate under such conditions.

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1203339109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427054PMC
August 2012
13 Reads

Publication Analysis

Top Keywords

demonstrate muc1
16
pancreatic cancer
16
cancer cells
12
muc1
11
glucose metabolism
8
involved glucose
8
cancer
8
muc1 acts
8
muc1 expression
8
glucose uptake
8
cancer cell
8
indicate muc1
8
expression enhances
8
promoter elements
8
hif-1α p300
8
glucose
5
pancreatic
5
metabolism
5
factor-1α hif-1α
4
hypoxia-inducible factor-1α
4

Similar Publications

MUC1 regulates PDGFA expression during pancreatic cancer progression.

Oncogene 2012 Nov 23;31(47):4935-45. Epub 2012 Jan 23.

Department of Biology, University of North Carolina, Charlotte, NC 28223, USA.

Pancreatic ductal adenocarcinoma (PDA) has one of the worst prognoses of all cancers. Mucin 1 (MUC1), a transmembrane mucin glycoprotein, is a key modulator of several signaling pathways that affect oncogenesis, motility and metastasis. Its expression is known to be associated with poor prognosis in patients. Read More

View Article
November 2012

MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer.

Cancer Cell 2017 07;32(1):71-87.e7

Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address:

Poor response to cancer therapy due to resistance remains a clinical challenge. The present study establishes a widely prevalent mechanism of resistance to gemcitabine in pancreatic cancer, whereby increased glycolytic flux leads to glucose addiction in cancer cells and a corresponding increase in pyrimidine biosynthesis to enhance the intrinsic levels of deoxycytidine triphosphate (dCTP). Increased levels of dCTP diminish the effective levels of gemcitabine through molecular competition. Read More

View Article
July 2017

Mucin 1 oncoprotein blocks hypoxia-inducible factor 1alpha activation in a survival response to hypoxia.

J Biol Chem 2007 Jan 13;282(1):257-66. Epub 2006 Nov 13.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.

Resistance of carcinoma cells to hypoxic stress is of importance to the growth of solid tumors. The mucin 1 (MUC1) oncoprotein is aberrantly overexpressed by most human carcinomas; however, there is no known relationship between MUC1 and the hypoxic stress response. The present work has demonstrated that MUC1 attenuates activation of hypoxia-inducible factor-1alpha (HIF-1alpha), a regulator of gene transcription in the response of cells to hypoxic stress. Read More

View Article
January 2007

MUC1-Mediated Metabolic Alterations Regulate Response to Radiotherapy in Pancreatic Cancer.

Clin Cancer Res 2017 Oct 18;23(19):5881-5891. Epub 2017 Jul 18.

The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.

, an oncogene overexpressed in multiple solid tumors, including pancreatic cancer, reduces overall survival and imparts resistance to radiation and chemotherapies. We previously identified that MUC1 facilitates growth-promoting metabolic alterations in pancreatic cancer cells. The present study investigates the role of MUC1-mediated metabolism in radiation resistance of pancreatic cancer by utilizing cell lines and models. Read More

View Article
October 2017