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

J Exp Clin Cancer Res. 2018 Sep 4;37(1):216. doi: 10.1186/s13046-018-0892-2.

Abstract

Background: Hypoxia-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.

Methods: We 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.

Results: In 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.

Conclusions: Our findings describe a new regulatory mechanism of hypoxia-mediated HCC metabolism, and YAP might be a promising therapeutic target in HCC.

Keywords: Glycolysis; HCC; HIF-1α; Hypoxia; Yes-associated protein (YAP).

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Carrier Proteins / genetics*
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Glycolysis
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Male
  • Membrane Proteins / genetics*
  • Phosphoproteins / genetics*
  • Phosphorylation
  • Protein Stability
  • RNA, Messenger / genetics
  • Signal Transduction / genetics
  • Stress, Physiological / genetics
  • Thyroid Hormones / genetics*
  • Transcription Factors
  • Tumor Hypoxia / genetics
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Membrane Proteins
  • Phosphoproteins
  • RNA, Messenger
  • Thyroid Hormones
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • thyroid hormone-binding proteins