The role and mechanism of hypoxia-induced SLC6A8 up-regulation in HCC progression
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PROVIDER: PRJNA1224831 | ENA |
REPOSITORIES: ENA
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Project description:Hepatocellular carcinoma (HCC) is a formidable malignancy with limited effective therapeutic avenues. This study was designed to investigate the role of transglutaminase 2 (TGM2) in promoting HCC progression and assess its potential as a target for therapeutic intervention in HCC treatment.TMG2 expression was positively related to a higher AFP level, poor differentiation, and a later BCLC stage. Tgm2 deficiency or H3Q5ser inhibition notably restrained HCC progression. Mechanism research revealed that TGM2-mediated H3Q5ser modifications promote HCC progression via MYC pathway signaling. Furthermore, transcriptional intermediary factor 1 beta (TIF1-β/TRIM28) mediated the recruitment of TGM2 by MYC to facilitate H3Q5ser modifications on MYC targets. Finally, targeting the TGM2 transglutaminase activity significantly suppressed HCC progression in preclinical models.
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Project description:Recently, a PARP1-dependent cell-death process termed "parthanatos", driven by DNA damage, has emerged as a crucial regulator of tissue homeostasis and tumorigenesis. Hypoxia is a hallmark of solid tumors and profoundly affects the malignant phenotypes of cancer cells. The crosstalk between parthanatos and hypoxia remains poorly understood. In our study, we find that despite causing DNA damage, hypoxia fails to induce parthanatos in HCC. Transcriptome sequencing upon MNNG stimulation indicated that the creatine transporter solute carrier family 6, member 8 (SLC6A8) was involved in parthanatos antagonism and malignant phenotypes in hypoxic HCC cells.
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