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Pan-HDAC Inhibition Reverses the Warburg Effect and Leads to Metabolic Vulnerabilities

ABSTRACT: Pan-HDAC Inhibition Reverses the Warburg Effect and Leads to Metabolic Vulnerabilities

PROVIDER: PRJNA514055 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8428290.fastq.gz	Fastqsanger.gz
	SRR8428300.fastq.gz	Fastqsanger.gz
	SRR8428291.fastq.gz	Fastqsanger.gz
	SRR8428301.fastq.gz	Fastqsanger.gz
	SRR8428292.fastq.gz	Fastqsanger.gz

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Pan-HDAC Inhibition Reverses the Warburg Effect and Leads to Metabolic Vulnerabilities

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Project description:Altered glycolysis is the most fundamental metabolic change associated with the Warburg effect. However, the precise mechanisms are not completely understood. Here we dissect how MNX1-AS1 reinforces the Warburg effect through facilitating the non-glycolytic actions of PKM2 in the nucleus. We found that MNX1-AS1 expression was frequently overexpressed in hepatocellular carcinoma (HCC). In the context of HCC, we show MNX1-AS1 acts as a scaffold to promote interactions between PKM2 and importin α5. Upon EGFR activation, the resulting ternary complex drives the translocation of PKM2 into the nucleus. In consequence, glycolytic pathway components including key mediators of the Warburg effect (LDHA, Glut1 and PDK1) are upregulated. Manipulating MNX1-AS1 elicited robust effects on glycolysis associated with marked changes in HCC growth in vitro and in vivo, indicative of the significant contribution of MNX1-AS1 to tumorigenesis. Moreover, while MNX1-AS1 expression is driven by c-Myc, its actions associated with PKM2 were shown to be downstream and independent of c-Myc. Given the status of MNX1-AS1 as a pan-cancer upregulated lncRNA, this implicitly highlights the potential of targeting MNX1-AS1 to selectively counter the Warburg effect in a range of tumor types.

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