Oncotarget

Research Papers:

Upregulation of lactate dehydrogenase a by 14-3-3ζ leads to increased glycolysis critical for breast cancer initiation and progression

Chia-Chi Chang _, Chenyu Zhang, Qingling Zhang, Ozgur Sahin, Hai Wang, Jia Xu, Yi Xiao, Jian Zhang, Sumaiyah K. Rehman, Ping Li, Mien-Chie Hung, Fariba Behbod, Dihua Yu

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Oncotarget. 2016; 7:35270-35283. doi: 10.18632/oncotarget.9136

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Abstract

Chia-Chi Chang1,2, Chenyu Zhang1, Qingling Zhang1, Ozgur Sahin1, Hai Wang1, Jia Xu1, Yi Xiao1, Jian Zhang1, Sumaiyah K. Rehman1, Ping Li1, Mien-Chie Hung1,2, Fariba Behbod3, Dihua Yu1,2

1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

2Cancer Biology Program, Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA

3Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA

Correspondence to:

Dihua Yu, e-mail: dyu@mdanderson.org

Keywords: LDHA, 14-3-3ζ, glycolysis, cancer metabolism, breast cancer initiation

Received: February 17, 2016    Accepted: April 16, 2016    Published: May 2, 2016

ABSTRACT

Metabolic reprogramming is a hallmark of cancer. Elevated glycolysis in cancer cells switches the cellular metabolic flux to produce more biological building blocks, thereby sustaining rapid proliferation. Recently, new evidence has emerged that metabolic dysregulation may occur at early-stages of neoplasia and critically contribute to cancer initiation. Here, our bioinformatics analysis of microarray data from early-stages breast neoplastic lesions revealed that 14-3-3ζ expression is strongly correlated with the expression of canonical glycolytic genes, particularly lactate dehydrogenase A (LDHA). Experimentally, increasing 14-3-3ζ expression in human mammary epithelial cells (hMECs) up-regulated LDHA expression, elevated glycolytic activity, and promoted early transformation. Knockdown of LDHA in the 14-3-3ζ-overexpressing hMECs significantly reduced glycolytic activity and inhibited transformation. Mechanistically, 14-3-3ζ overexpression activates the MEK-ERK-CREB axis, which subsequently up-regulates LDHA. In vivo, inhibiting the activated the MEK/ERK pathway in 14-3-3ζ-overexpressing hMEC-derived MCF10DCIS.COM lesions led to effective inhibition of tumor growth. Therefore, targeting the MEK/ERK pathway could be an effective strategy for intervention of 14-3-3ζ-overexpressing early breast lesions. Together, our data demonstrate that overexpression of 14-3-3ζ in early stage pre-cancerous breast epithelial cells may trigger an elevated glycolysis and transcriptionally up-regulating LDHA, thereby contributes to human breast cancer initiation.

Author Information

Chia-Chi Chang
Primary Contact  _

Chenyu Zhang

Qingling Zhang

Ozgur Sahin

Hai Wang

Jia Xu

Yi Xiao

Jian Zhang

Sumaiyah K. Rehman

Ping Li

Mien-Chie Hung

Fariba Behbod

Dihua Yu


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