Abstract
Cancer cells adapt to hypoxia through HIFs (hypoxia-inducible factors), which initiate the transcription of numerous genes for cancer cell survival in the hypoxia microenvironment. In this study, we find that the FACT (facilitates chromatin transcription) complex works cooperatively with HIFs to facilitate the expeditious expression of HIF targets for hypoxia adaptation. Knockout (KO) of the FACT complex abolishes HIF-mediated transcription by impeding transcription elongation in hypoxic cancer cells. Interestingly, the FACT complex is post-translationally regulated by PHD/VHL-mediated hydroxylation and proteasomal degradation, in similar fashion to HIF-1/2α. Metabolic tracing confirms that FACT KO suppresses glycolytic flux and impairs lactate extrusion, leading to intracellular acidification and apoptosis in cancer cells. Therapeutically, hepatic artery ligation and anti-angiogenic inhibitors adversely induce intratumoral hypoxia, while co-treatment with FACT inhibitor curaxin remarkably hinders the growth of hypoxic tumors. In summary, our findings suggest that the FACT complex is a critical component of hypoxia adaptation and a therapeutic target for hypoxic tumors.
Highlights
Nucleosomes, 146-bp DNA-wrapped core histone octamers, are the fundamental unit of eukaryotic chromatin
Histone chaperone facilitates chromatin transcription (FACT) complex controls the transcriptional program of hypoxic cancer cells HIFs are the transcription factors that initiate the transcription of a cascade of genes in hypoxia
To explore the roles of the FACT complex during hypoxic adaptation in cancer, we stably knocked out the two subunits of the FACT complex, structure-specific recognition protein 1 (SSRP1) and SUPT16H, in hepatocellular carcinoma (HCC) cell line MHCC97L with two single-guide RNAs, respectively
Summary
Nucleosomes, 146-bp DNA-wrapped core histone octamers, are the fundamental unit of eukaryotic chromatin. The local density and distribution of nucleosomes within a chromosomal region determine the chromatin structure. Nucleosome density and distribution could be affected by many factors, which mainly include DNA methylation status, histone modification signatures, and chromatin remodeling complex activities. Nucleosomes are dynamically assembled and disassembled throughout the cell cycle. The dynamic nucleosome-recycling processes are regulated by various histone chaperones, which mediate the histone transportation, disposition, and removal as well as replacement of histone variants. These histone chaperone proteins are known to be crucial for different nucleosome-reorganization events during DNA replication, DNA damage repair, and gene transcription
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