A regulatory feedback loop between HIF-1α and PIM2 in HepG2 cells

Zhenhai Yu; Xiaoping Zhao; Yingying Ge; Teng Zhang; Liangqian Huang; Xiang Zhou; Lei Xie; Jianjun Liu; Gang Huang

doi:10.1371/journal.pone.0088301

A regulatory feedback loop between HIF-1α and PIM2 in HepG2 cells

PLoS One. 2014 Feb 5;9(2):e88301. doi: 10.1371/journal.pone.0088301. eCollection 2014.

Authors

Zhenhai Yu¹, Xiaoping Zhao², Yingying Ge³, Teng Zhang², Liangqian Huang⁴, Xiang Zhou², Lei Xie², Jianjun Liu², Gang Huang⁵

Affiliations

¹ School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
² Department of Nuclear Medicine, Ren ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
³ State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
⁴ Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China.
⁵ Department of Nuclear Medicine, Ren ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China ; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China ; Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China.

Abstract

To survive under hypoxic conditions, cancer cells remodel glucose metabolism to support tumor progression. HIF transcription factor is essential for cellular response to hypoxia. The underlying mechanism how HIF is constitutively activated in cancer cells remains elusive. In the present study, we characterized a regulatory feedback loop between HIF-1α and PIM2 in HepG2 cells. Serine/threonine kinase proto-oncogene PIM2 level was induced upon hypoxia in a HIF-1α-mediated manner in cancer cells. HIF-1α induced PIM2 expression via binding to the hypoxia-responsive elements (HREs) of the PIM2 promoter. In turn, PIM2 interacted with HIF-1α, especially a transactivation domain of HIF-1α. PIM2 as a co-factor but not an upstream kinase of HIF-1α, enhanced HIF-1α effect in response to hypoxia. The positive feedback loop between PIM2 and HIF-1α was correlated with glucose metabolism as well as cell survival in HepG2 cells. Such a regulatory mode may be important for the adaptive responses of cancer cells in antagonizing hypoxia during cancer progression.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Hypoxia
Gene Expression Regulation, Neoplastic
Glucose / metabolism
Hep G2 Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Neoplasms / genetics
Neoplasms / metabolism*
Promoter Regions, Genetic
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Proto-Oncogene Mas
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism*

Substances

Hypoxia-Inducible Factor 1, alpha Subunit
MAS1 protein, human
PIM2 protein, human
Proto-Oncogene Mas
Proto-Oncogene Proteins
Protein Serine-Threonine Kinases
Glucose

Grants and funding

The study was supported by research grants from 973 Project (No. 2012CB932604), New Drug Discovery Project (No. 2012ZX09506-001-005), Shanghai Leading Academic Discipline Project (No. S30203), National Natural Science Foundation of China (No. 81071180 & 81001008), Shanghai Pujiang Program (No. 13PJ1406000) and Science and Technology Commission of Shanghai Municipality (No. 134119a5600). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.