Biochemical and Biophysical Research Communications
MTA1 coregulator regulates LDHA expression and function in breast cancer
Introduction
Deregulated metabolism is one of the hallmarks of cancer [1]. Cancer cells rely on glycolysis and exhibit reduced use of oxidative phosphorylation (TCA cycle). This phenomenon is known as Warburg effect which results in preferential pyruvate to lactate conversion, a causal event for cancer progression [2]. Additionally, proliferating cancer cells also regulate the glucose and glutamine metabolism pathways, which contribute to precursors for the biosynthesis of lipids and nucleic acids [3,4]. Lactate dehydrogenase A (LDHA), a key enzyme involved in the Warburg effect converts pyruvate to lactate and NADH to NAD+ [5]. Aberrant expression and activation of LDHA is closely associated with many cancers [[6], [7], [8]]. LDHA has been considered as a target for therapeutic intervention due to its critical role in metabolic reprogramming. LDHA expression was activated in various cancers and found to be regulated by several transcriptional factors including c-Myc, HIF1α, CREB, FOXM1, KLF4 and AP1 [[9], [10], [11], [12], [13], [14]]. Higher levels of LDHA were observed in malignant tumors compared to normal tissues [15]. Several studies reported that LDHA plays an important role in cancer cell growth, invasion and metastasis of malignant tumors [[16], [17], [18]]. The LDHA expression is positively correlated with the cancer prognosis and levels are elevated in metastatic cancers and therefore reported as a marker for the diagnosis and prognosis of cancers [19].
MTA1 is a transcriptional regulator and it is identified as a chromatin modifier, as it plays a key role in cancer progression, invasion and metastasis [20,21]. MTA1 was first identified while screening the cDNA library of rat mammary adenocarcinoma metastatic model as an up-regulated gene [22]. Subsequent studies reported that MTA1 is upregulated in almost all types of human cancers and its expression is positively correlated with tumor invasion and migration [20,21]. MTA1 was found to be instrumental in promoting transformation, epithelial to mesenchymal transition and metastasis [[23], [24], [25]]. Down regulation of MTA1 expression suppressed tumor migration and invasion in various cancer models [[26], [27], [28]]. However, it is unclear whether MTA1 has any significant role in glucose metabolism in order to drive the cancer invasion and migration.
In this study, we investigated the role of MTA1 in glucose metabolism. MTA1 was found to interact with the genes involved in glucose metabolism. It was also found that MTA1 regulates LDHA expression and activity in breast cancer. Overexpression of MTA1 increased the expression and activity of LDHA whereas knockdown of MTA1 decreased the expression and activity of LDHA. Further, MTA1 was found to interact with c-Myc and thereby regulates LDHA transcription and in turn the migratory function of LDHA. These findings demonstrated a novel regulatory role for MTA1 in glucose metabolism. Hence, targeting MTA1-LDHA axis could be a potential strategy for breast cancer therapy.
Section snippets
Cell culture, antibodies and other reagents
All the cell lines used in this study were kindly provided by Dr. Rayala Suresh Kumar, IIT Madras, Chennai, India. MCF7, MDA- MB-231 and BT-474 were cultured in DMEM supplemented with 10% fetal bovine serum (FBS) and 1X antibiotic solution. SKBR3 cells and BT549 were cultured in RPMI medium (RPMI 1640) containing 10% FBS and 1 X antibiotic solution. MCF7 stable clones expressing pcDNA3.1 empty vector (MCF7/pcDNA) and MTA1 (MCF-7/MTA1) were generated in our laboratory and were maintained in DMEM
MTA1 interacts with the genes of glucose metabolism
The MTA1-glucose metabolism and transport interactome were extracted from different databases such as STRING, GeneMANIA, BioGRID and INTACT. Only interactions that have experimental evidence through small scale and large-scale experiments such as affinity purification, pull-down assays, co-localization or high-throughput techniques (S1 Dataset) were extracted. Careful examination of the gene ontology terms associated with the MTA1 interactome (S2 Dataset) shows that MTA1 has direct interactions
Discussion
In summary, our findings demonstrate that MTA1 interacts with the genes of glucose metabolism via MYC and MAX. Regulation of LDHA by MTA1 has introduced a new regulatory player in the event of glycolysis, invasion and migration. Although there are several studies on the overexpression of LDHA and its involvement in cancer cell invasion and migration [5,[9], [10], [11], [12], [13], [14],38], not much is known about LDHA transcriptional regulation. In this context, the present study has
Conflicts of interest
The authors declare that they have no conflict interests.
Acknowledgements
Indian Institute of Science Education and Research (IISER) Tirupati and SERB, New Delhi (SB/YS/LS-57/2014) supported this work. We are thankful to Prof. B. J. Rao for fruitful discussions and constant encouragement. We are grateful to Dr. Joel Mackay, University of Sydney, Australia for kindly providing MTA1 construct cloned in pcDNA3. We are thankful to Dr. Nanda Kumar Yellapu, Vector Control Research Center-ICMR, Pondicherry for helping in Molecular docking studies. We are thankful to Dr.
References (38)
- et al.
Hallmarks of cancer: the next generation
Cell
(2011) - et al.
Brick by brick: metabolism and tumor cell growth
Curr. Opin. Genet. Dev.
(2008) - et al.
Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance
Cancer Cell
(2006) - et al.
Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1
J. Biol. Chem.
(1996) - et al.
Transcriptional regulation of the lactate dehydrogenase A subunit gene by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate
Mol. Cell. Endocrinol.
(1995) - et al.
Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer
Int. J. Radiat. Oncol. Biol. Phys.
(2001) - et al.
Serum lactic dehydrogenase strongly predicts survival in metastatic nasopharyngeal carcinoma treated with palliative chemotherapy
Eur. J. Cancer
(2013) - et al.
Metastasis tumor antigens, an emerging family of multifaceted master coregulators
J. Biol. Chem.
(2007) - et al.
A novel candidate metastasis-associated gene, mta1, differentially expressed in highly metastatic mammary adenocarcinoma cell lines. cDNA cloning, expression, and protein analyses
J. Biol. Chem.
(1994) - et al.
MTA1 coregulator regulates LPS response via MyD88-dependent signaling
J. Biol. Chem.
(2010)
Molecular mechanism of regulation of MTA1 expression by granulocyte Colony-stimulating factor
J. Biol. Chem.
13C-pyruvate imaging reveals alterations in glycolysis that precede c-Myc-induced tumor formation and regression
Cell Metabol.
On the origin of cancer cells
Science
Understanding the Warburg effect: the metabolic requirements of cell proliferation
Science
Lactate dehydrogenase A: a key player in carcinogenesis and potential target in cancer therapy
Cancer Med.
Knockdown of lactate dehydrogenase A suppresses tumor growth and metastasis of human hepatocellular carcinoma
FEBS J.
Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression
Proc. Natl. Acad. Sci. U. S. A.
c-Myc transactivation of LDH-A: implications for tumor metabolism and growth
Proc. Natl. Acad. Sci.
Analysis of the rat lactate dehydrogenase A subunit gene promoter/regulatory region
Biochem. J.
Cited by (18)
Chemical proteomics reveals interactors of the alarmone diadenosine triphosphate in the cancer cell line H1299<sup>†</sup>
2023, Journal of Peptide ScienceBuffalo Milk Whey Activates Necroptosis and Apoptosis in a Xenograft Model of Colorectal Cancer
2022, International Journal of Molecular SciencesMetastasis-associated protein 1: A potential driver and regulator of the hallmarks of cancer
2022, Journal of Biosciences
- 1
These authors contributed equally to the present work.