Yes-associated protein (YAP) binds to HIF-1\u03b1 and sustains HIF-1\u03b1 protein stability to promote hepatocellular carcinoma cell glycolysis under hypoxic stress

Xiaodong Zhang,Yan Li,Xiangdong Hua,Tao Wang,Xun Sun,Yingbo Ma,Liang Yang,Hangyu Li,Zhihong Zong,Xin Meng

doi:10.1186/s13046-018-0892-2

Abstract

BackgroundHypoxia-inducible factor 1α (HIF-1α) is essential in hepatocellular carcinoma (HCC) glycolysis and progression. Yes-associated protein (YAP) is a powerful regulator and is overexpressed in many cancers, including HCC. The regulatory mechanism of YAP and HIF-1α in HCC glycolysis is unknown.MethodsWe detected YAP expression in 54 matched HCC tissues and the adjacent noncancerous tissues. The relationship between YAP mRNA expression and that of HIF-1α was analyzed using The Cancer Genome Atlas HCC tissue data. We cultured HepG2 and Huh7 HCC cells under normoxic (20% O2) and hypoxic (1% O2) conditions, and measured the lactate and glucose levels, migration and invasive capability, and the molecular mechanism of HCC cell glycolysis and progression.ResultsIn this study, we detected YAP expression in 54 matched HCC tissues and the adjacent noncancerous tissues. We observed that hypoxia-induced YAP activation is crucial for accelerating HCC cell glycolysis. Hypoxia inhibited the Hippo signaling pathway and promoted YAP nuclear localization, and decreased phosphorylated YAP expression in HCC cells. YAP knockdown inhibited HCC cell glycolysis under hypoxic. Mechanistically, hypoxic stress in the HCC cells promoted YAP binding to HIF-1α in the nucleus and sustained HIF-1α protein stability to bind to PKM2 gene and directly activates PKM2 transcription to accelerate glycolysis.ConclusionsOur findings describe a new regulatory mechanism of hypoxia-mediated HCC metabolism, and YAP might be a promising therapeutic target in HCC.

Highlights

Hypoxia-inducible factor 1α (HIF-1α) is essential in hepatocellular carcinoma (HCC) glycolysis and progression
The results obtained from real-time PCR showed significantly increased Yes-associated protein (YAP) mRMA levels in the tumor tissues as compared with the adjacent noncancerous tissues (p = 0.006, Fig. 1a); Immunohistochemical staining revealed 53.7% (29/54) HCC tissues were positive for YAP expression, whereas only 18.5% (10/54) adjacent normal tissues were positive for YAP expression (Fig. 1b)
The glucose and lactate assays were performed and the results showed that hypoxia significantly increased HCC cell glucose uptake and lactate production rates, respectively, Fig. 2 YAP correlated strongly with HIF-1α. a Gene set enrichment analysis (GSEA) indicated a significantly enhanced expression of Hippo signaling genes in HCC tissues from the The Cancer Genome Atlas (TCGA) database. b The expression of YAP mRNA is positively correlated with the expression of HIF-1α mRNA in 369 cases of HCC tissues from TCGA, which were analysed by Gene Expression Profiling Interactive Analysis (GEPIA). c Real-time PCR showed YAP mRNA correlated strongly with HIF-1α mRNA in 54 pairs of HCC tissues. d Western blot showed the representative expression of YAP and HIF-1α in HCC tissues and adjacent tissues

Summary

Introduction

Hypoxia-inducible factor 1α (HIF-1α) is essential in hepatocellular carcinoma (HCC) glycolysis and progression. The regulatory mechanism of YAP and HIF-1α in HCC glycolysis is unknown. One of the commonest cancers is hepatocellular carcinoma (HCC); in 2015, it was the primary cause of cancer death in men under 60 years of age [1]. HCC, and other solid tumors, has the common feature of fast growth. Tumor cells exist in a hypoxic environment, which is a fundamental solid tumor microenvironment characteristic. Such cells adapt to hypoxic stress by altering their glucose metabolism from oxidation to glycolysis, which provides sufficient energy and materials for cancer cell anabolic growth. There is an essential role for hypoxia-inducible factor 1α

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