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

Abstract

Hypoxia is commonly found in cancers. Hypoxia, due to the lack of oxygen (O2) 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 O2. 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.

Identification of a Hypoxia-Associated Signature for Lung Adenocarcinoma

“…Hypoxia is a typical characteristic observed in the tumor microenvironment and drives the aggressiveness of many tumors, such as hepatocellular carcinoma (Kung-Chun Chiu et al, 2019), colorectal cancer (Qureshi-Baig et al, 2019), and esophageal squamous cell carcinoma (Zhang et al, 2019). Under hypoxic conditions, many transcription factors are activated in tumor cells, inducing various downstream signals regulating cell proliferation, motility, and apoptosis (Semenza, 2012).…”

<p>Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect</p>

“…[32][33][34] In a hypoxic environment, the low oxygen content and the lack of oxygen as electron recipient lead to the imbalance of electron flow through the mitochondrial electron chain, which contributes to the accumulation of ROS and causes irreversible cellular damages in tumors. 35,36 However, HIF-1α can promote HCC progression by preventing ROS accumulation through the following pathways. First, HIF-1α prevents pyruvate from entering TCA cycle by inactivating PDH through PDKs and the conversion of pyruvate to lactate by upregulating LDHA expression.…”

“…21,37,38 HIF-1α therapy ensures that circulating tricarboxylic acid cycle (TCA) substrates cannot enter mitochondrial oxidation. 36,39 Second, HIF-1α can reduces ROS accumulation by inhibiting ROS production sites in the electron transport chain (ETC), such as complexes 1 and 4. 40,41 Third, HIF-1α decreases the number of mitochondrial cristae and the mitochondrial mass through HEY1/PINK1 pathway, and degrading mitochondria by inducing BNIP3 to restrict ROS production and promote ROS elimination.…”

Autonomous glucose metabolic reprogramming of tumour cells under hypoxia: opportunities for targeted therapy

“…The HEY1 gene is an important member of the HEY family, which mainly functions to recruit corepressors for its target genes to inhibit transcription. Under hypoxia, HIF-1α can upregulate the expression of HEY1 and then recruit corepressors to inhibit the transcriptional activity of PINK1, reducing mitochondrial mass and promoting the growth of cancer cells [75]. In summary, the inhibition of mitochondrial biogenesis by HIF depends mainly on the regulation of key genes, such as c-Myc, PGC-1, and PINK1, which may also provide new therapeutic targets for future cancer treatment.…”