Abstract
Hypoxia is one of the main driving forces that results in poor outcomes and drug resistance in hepatocellular carcinoma (HCC). As the critical cellular oxygen sensor, mitochondria respond to hypoxic stress by sending retrograde signals to the nucleus that initiate adaptive metabolic responses and maintain the survival of HCC cells. Increasing evidence suggested autophagy contributes to sustain mitochondrial metabolic and quality control. Understanding how mitochondria communicate with the nucleus and alter transcription may provide promising targets for HCC treatment. In this study, we found mitochondrial undergoes selective degradation by autophagy under hypoxia. Furthermore, autophagy-activated HDAC6 not only promoted the nuclear translocation of β-catenin but also increased the affinity of β-catenin to the transcription repressor chicken ovalbumin upstream promoter-transcription factor 2 (COUP-TF II), which suppressed mitochondrial oxidative phosphorylation-related genes transcription. Our data showed that autophagy served as a critical mediator of integrating mitochondrial energy metabolism and nuclear transcription. HDAC6 may be a potential target for reducing the survival of HCC cells by interrupting mitochondria-nucleus crosstalk.
Highlights
Hepatocellular carcinoma (HCC) is one of the most malignant tumor types and the third leading cause of cancer-related death worldwide [1]
Our results found that, compared with normoxia (21% O2), hepatocellular carcinoma (HCC) cells showed increased viability with 1% oxygen treatment, which indicated that HCC cells may overcome normal barriers to proliferation, such as hypoxia, as they adapted to the everchanging hostile tumor microenvironment (Figure 1A)
Multi cellular organisms have evolved mechanisms to rapidly adapt to hypoxia, and these pathways have been co-opted to prolong the survival of HCC cells
Summary
Hepatocellular carcinoma (HCC) is one of the most malignant tumor types and the third leading cause of cancer-related death worldwide [1]. Recent studies have demonstrated that dysregulated and damaged mitochondria are removed by autophagy in a process termed mitophagy that is critical for mitochondrial quality control. During this process, mitochondria are encircled by double-membrane vesicles and delivered to lysosomes for degradation [7]. Previous studies in HCC have found that inhibiting mitophagy promoted p53 phosphorylation and nuclear translocation in hepatic cancer stem cells [8]. These studies indicated that dysregulated mitochondria-induced mitophagy may result in nuclear transcriptional responses. Communication between mitochondria and the nucleus controls metabolic homeostasis during stress, such as that from hypoxia
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