Hypoxia regulates the mitochondrial activity of hepatocellular carcinoma cells through HIF/HEY1/PINK1 pathway

• Published in: Cell death & disease Vol. 10; no. 12; pp. 934 - 16
• Main Authors: Kung-Chun Chiu, David, Pui-Wah Tse, Aki, Law, Cheuk-Ting, Ming-Jing Xu, Iris, Lee, Derek, Chen, Mengnuo, Kit-Ho Lai, Robin, Wai-Hin Yuen, Vincent, Wing-Sum Cheu, Jacinth, Wai-Hung Ho, Daniel, Wong, Chun-Ming, Zhang, Huafeng, Ng, Irene Oi-Lin, Chak-Lui Wong, Carmen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.12.2019; Springer Nature B.V
• Subjects: 13; 13/1; 13/106; 13/109; 13/31; 13/51; 14; 14/28; 38; 631/67/2327; 631/80/86/2366; Animals; Antibodies; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biochemistry; Biomedical and Life Sciences; Biosynthesis; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Biology; Cell Culture; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Hypoxia - genetics; Chromatin; Cristae; Electron transfer; Electron transport chain; Gene expression; HeLa Cells; Hep G2 Cells; Hepatocellular carcinoma; Heterografts; Humans; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factors; Immunology; Immunoprecipitation; Life Sciences; Liver cancer; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Mitochondria; Mitochondria - metabolism; Molecular modelling; Oxidative stress; Protein Kinases - genetics; Protein Kinases - metabolism; PTEN-induced putative kinase; Reactive oxygen species; Regulatory sequences; Therapeutic applications; Transcription; Transcriptomes; Transfection; Tumor Burden - genetics; Tumors
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-2155-3

Hypoxia is commonly found in cancers. Hypoxia, due to the lack of oxygen (O 2 ) as the electron recipient, causes inefficient electron transfer through the electron transport chain at the mitochondria leading to accumulation of reactive oxygen species (ROS) which could create irreversible cellular damages. Through hypoxia-inducible factor 1 (HIF-1) which elicits various molecular events, cells are able to overcome low O 2 . Knowledge about the new molecular mechanisms governed by HIF-1 is important for new therapeutic interventions targeting hypoxic tumors. Using hepatocellular carcinoma (HCC) as a model, we revealed that the HIF-1 and the Notch signaling pathways cross-talk to control mitochondrial biogenesis of cancer cells to maintain REDOX balance. From transcriptome sequencing, we found that HEY1, a transcriptional repressor, in the NOTCH pathway was consistently induced by hypoxia in HCC cell lines. We identified a strong hypoxia response element (HRE) in HEY1 by chromatin immunoprecipitation (ChIP) and luciferase reporter assays. Transcriptome and ChIP sequencing further identified PINK1, a gene essential for mitochondrial biogenesis, as a novel transcriptional target of HEY1. HCC cells with HEY1 knockdown re-expressed PINK1. HEY1 and PINK1 expressions inversely correlated in human HCC samples. Overexpression of HEY1 and under-expression of PINK1 were detected in human HCC and associated with poor clinical outcomes. Functionally, we found that overexpression of HEY1 or knockdown of PINK1 consistently reduced mitochondrial cristae, mitochondrial mass, oxidative stress level, and increased HCC growth.