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Super-enhancer-driven MLX mediates redox balance maintanance via SLC7A11 in osteosarcoma

ABSTRACT: Super-enhancer-driven MLX mediates redox balance maintanance via SLC7A11 in osteosarcoma

PROVIDER: PRJNA909175 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22543763_1.fastq.gz	Fastqsanger.gz
	SRR22543763_2.fastq.gz	Fastqsanger.gz
	SRR22543764_1.fastq.gz	Fastqsanger.gz
	SRR22543764_2.fastq.gz	Fastqsanger.gz
	SRR22543765_1.fastq.gz	Fastqsanger.gz

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Super-enhancer-driven MLX mediates redox balance maintanance via SLC7A11 in osteosarcoma

Project description:A systematic analysis of super-enhancers identified MLX as a potential oncogene in osteosarcoma. Knockdown of MLX impaired tumor aggressiveness in vitro and in vivo, suggesting oncogenic properties of MLX. Mechanistically, silencing of MLX downregulates SLC7A11, a key gene encoding glutamate/cystine antiporter, to attenuate the uptake of cystine and interrupt the redox balance, leading to ferroptotic cell death. Pharmacological inhibition of SLC7A11 triggered massive ferroptosis and caused impaired tumor growth, providing a promising approach for osteosarcoma treatment.

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Super-enhancer-driven MLX mediates redox balance maintenance via SLC7A11 in osteosarcoma.

Project description:Osteosarcoma (OS) is a common type of bone tumor for which there has been limited therapeutic progress over the past three decades. The prevalence of transcriptional addiction in cancer cells emphasizes the biological significance and clinical relevance of super-enhancers. In this study, we found that Max-like protein X (MLX), a member of the Myc-MLX network, is driven by super-enhancers. Upregulation of MLX predicts a poor prognosis in osteosarcoma. Knockdown of MLX impairs growth and metastasis of osteosarcoma in vivo and in vitro. Transcriptomic sequencing has revealed that MLX is involved in various metabolic pathways (e.g., lipid metabolism) and can induce metabolic reprogramming. Furthermore, knockdown of MLX results in disturbed transport and storage of ferrous iron, leading to an increase in the level of cellular ferrous iron and subsequent induction of ferroptosis. Mechanistically, MLX regulates the glutamate/cystine antiporter SLC7A11 to promote extracellular cysteine uptake required for the biosynthesis of the essential antioxidant GSH, thereby detoxifying reactive oxygen species (ROS) and maintaining the redox balance of osteosarcoma cells. Importantly, sulfasalazine, an FDA-approved anti-inflammatory drug, can inhibit SLC7A11, disrupt redox balance, and induce massive ferroptosis, leading to impaired tumor growth in vivo. Taken together, this study reveals a novel mechanism in which super-enhancer-driven MLX positively regulates SLC7A11 to meet the alleviated demand for cystine and maintain the redox balance, highlighting the feasibility and clinical promise of targeting SLC7A11 in osteosarcoma.

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A novel MYC-ZNF706-SLC7A11 regulatory circuitry contributes to cancer progression and redox balance in human hepatocarcinoma (ChIP-Seq)

Project description:ZNF706 belongs to a member of C2H2-type zinc finger proteins which exerts pivotal roles in cancer progression. However, the biological function and mechanism of ZNF706 are rarely investigated. Using qRT-PCR and Western blot assays, we identified ZNF706 was frequently amplified in human hepatocarcinoma and high ZNF706 expression was associated with unfavorable HCC patient survival based on TCGA database. In vitro and in vivo experiments revealed that ZNF706 promoted HCC cell growth. Mechanistically, RNA-seq and ChIP-seq identified SLC7A11 was a critical target of ZNF706, and depletion of ZNF706 increased lipid peroxidation, cell death and decreased cystine uptake medicated by SLC7A11 contributing to redox homeostasis disruption. Furthermore, using luciferase report assays and ChIP-qPCR, we found MYC could regulate ZNF706 transcription by binding to ZNF706 promoter region, and further assay indicated MYC also involved in redox balance by modulating SLC7A11. Collectively, our study uncovers that the oncogenic role of ZNF706 in liver cancer, indicating that ZNF706 inhibition could be a potential treatment strategy for liver cancer.

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A novel MYC-ZNF706-SLC7A11 regulatory circuitry contributes to cancer progression and redox balance in human hepatocarcinoma

Project description:A novel MYC-ZNF706-SLC7A11 regulatory circuitry contributes to cancer progression and redox balance in human hepatocarcinoma

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A novel MYC-ZNF706-SLC7A11 regulatory circuitry contributes to cancer progression and redox balance in human hepatocarcinoma (ChIP-Seq)

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