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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.

SUBMITTER: Kung-Chun Chiu D

PROVIDER: S-EPMC6901483 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Kung-Chun Chiu David D Pui-Wah Tse Aki A Law Cheuk-Ting CT Ming-Jing Xu Iris I Lee Derek D Chen Mengnuo M Kit-Ho Lai Robin R Wai-Hin Yuen Vincent V Wing-Sum Cheu Jacinth J Wai-Hung Ho Daniel D Wong Chun-Ming CM Zhang Huafeng H Ng Irene Oi-Lin IO Chak-Lui Wong Carmen C

Cell death & disease 20191209 12

Hypoxia is commonly found in cancers. Hypoxia, due to the lack of oxygen (O<sub>2</sub>) 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<sub>2</sub>. Knowledge about the new molecular mechanisms governed ...[more]

PMID: 31819034

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Project description:BackgroundHypoxia naturally happens in embryogenesis and thus serves as an important environmental factor affecting embryo development. Hif-1α, an essential hypoxia response factor, was mostly considered to mediate or synergistically regulate the effect of hypoxia on stem cells. However, the function and relationship of hypoxia and Hif-1α in regulating mesendoderm differentiation remains controversial.ResultsWe here discovered that hypoxia dramatically suppressed the mesendoderm differentiation and promoted the ectoderm differentiation of mouse embryonic stem cells (mESCs). However, hypoxia treatment after mesendoderm was established promoted the downstream differentiation of mesendoderm-derived lineages. These effects of hypoxia were mediated by the repression of the Wnt/β-Catenin pathway and the Wnt/β-Catenin pathway was at least partially regulated by the Akt/Gsk3β axis. Blocking the Wnt/β-Catenin pathway under normoxia using IWP2 mimicked the effects of hypoxia while activating the Wnt/β-Catenin pathway with CHIR99021 fully rescued the mesendoderm differentiation suppression caused by hypoxia. Unexpectedly, Hif-1α overexpression, in contrast to hypoxia, promoted mesendoderm differentiation and suppressed ectoderm differentiation. Knockdown of Hif-1α under normoxia and hypoxia both inhibited the mesendoderm differentiation. Moreover, hypoxia even suppressed the mesendoderm differentiation of Hif-1α knockdown mESCs, further implying that the effects of hypoxia on the mesendoderm differentiation were Hif-1α independent. Consistently, the Wnt/β-Catenin pathway was enhanced by Hif-1α overexpression and inhibited by Hif-1α knockdown. As shown by RNA-seq, unlike hypoxia, the effect of Hif-1α was relatively mild and selectively regulated part of hypoxia response genes, which fine-tuned the effect of hypoxia on mESC differentiation.ConclusionsThis study revealed that hypoxia is fine-tuned by Hif-1α and regulates the mesendoderm and ectoderm differentiation by manipulating the Wnt/β-Catenin pathway, which contributed to the understanding of hypoxia-mediated regulation of development.

Project description:The ability of cancer cells to survive and grow under hypoxic conditions has been known for decades, but the mechanisms remain poorly understood. Under certain conditions, cancer cells undergo changes in their bioenergetic profile to favor mitochondrial respiration by activating the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and up-regulating mitochondrial biogenesis. In this study, we hypothesized that augmented mitochondrial biogenesis plays a critical role for cancer cells to survive hypoxia. Consistent with this hypothesis, both hypoxic human hepatocellular carcinoma (HCC) tumors and HCC cell lines subjected to hypoxia increase mitochondrial biogenesis. Silencing of PGC-1α in hypoxic HCC cell lines halts their proliferation. Mechanistic investigations in vitro indicated that intracellular high mobility group box 1 (HMGB1) protein, a nuclear protein overexpressed in HCC, is essential for the process. Silencing of HMGB1 in hypoxic HCC cell lines resulted in a significant decrease in PGC-1α activation and mitochondrial biogenesis. Without HMGB1, hypoxic HCC cells had significantly reduced adenosine triphosphate production, decreased cellular proliferation, and increased apoptosis. In a diethylnitrosamine-induced murine model of HCC, genetic blocking of HMGB1 in hypoxic tumors resulted in a significant decrease in tumor growth. Tumors lacking HMGB1 had a significant reduction in mitochondrial biogenesis and a significant increase in mitochondrial dysfunction. Further in vitro mechanistic experiments indicated that during hypoxia HMGB1 translocates from the nucleus to the cytoplasm and binds to cytoplasmic Toll-like receptor-9. This binding leads to activation of p38 and subsequent phosphorylation of PGC-1α, with resultant up-regulation of mitochondrial biogenesis.ConclusionTaken together, our findings suggest that during hypoxia HMGB1 up-regulates mitochondrial biogenesis in HCC cancer cells, promoting tumor survival and proliferation. (Hepatology 2017;66:182-197).

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

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

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