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<p>Insulin promotes HepG2 cell proliferation by inducing phosphorylation of the pyruvate dehydrogenase E1α (PDHA1) subunit at Ser293, a mechanism distinct from normal liver tissue. This study investigates how phosphorylated PDHA1 drives hepatocellular carcinoma cell proliferation. We identified eukaryotic elongation factor-1γ (eEF-1γ) as a key binding protein interacting with p-PDHA1 in response to insulin, facilitating their nuclear translocation. Silencing eEF-1γ (si-eEF-1γ) significantly reduced p-PDHA1 and PKM2 levels, highlighting eEF-1γ’s role in stabilizing these proteins. Additionally, eEF-1γ interacts with ATP-citrate lyase (ACL) and p300 acetyltransferase, and its knockdown decreased histone acetylation at H3K9/14, H3K18, and H3K27, along with RBP4 expression. Chromatin immunoprecipitation PCR (ChIP-PCR) confirmed eEF-1γ association with RBP4 promoter. Functionally, si-eEF-1γ reduced cell proliferation and deceased c-Myc and cyclin D1 protein levels. It also suppressed migration, and altered epithelial-mesenchymal transition (EMT) markers, increasing E-cadherin while reducing ZEB1, snail1, vimentin, and N-cadherin levels. Similarly, RBP4 knockdown with siRNA diminished cell proliferation and migration. In vivo, eEF-1γ knockdown in 4T1 xenografts using siRNA led to reduced tumor mass. These findings highlight eEF-1γ as a crucial driver of insulin-induced tumor progression and suggest its potential as a therapeutic target in hepatocellular carcinoma.</p>

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Function of eEF-1γ in the nucleus in response to insulin in hepatocellular carcinoma cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月29日

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  • Abu Jubayer Hossain,
  • Amir Hamza,
  • Rokibul Islam,
  • Oyungerel Dogsom,
  • Jae-Bong Park

摘要

Insulin promotes HepG2 cell proliferation by inducing phosphorylation of the pyruvate dehydrogenase E1α (PDHA1) subunit at Ser293, a mechanism distinct from normal liver tissue. This study investigates how phosphorylated PDHA1 drives hepatocellular carcinoma cell proliferation. We identified eukaryotic elongation factor-1γ (eEF-1γ) as a key binding protein interacting with p-PDHA1 in response to insulin, facilitating their nuclear translocation. Silencing eEF-1γ (si-eEF-1γ) significantly reduced p-PDHA1 and PKM2 levels, highlighting eEF-1γ’s role in stabilizing these proteins. Additionally, eEF-1γ interacts with ATP-citrate lyase (ACL) and p300 acetyltransferase, and its knockdown decreased histone acetylation at H3K9/14, H3K18, and H3K27, along with RBP4 expression. Chromatin immunoprecipitation PCR (ChIP-PCR) confirmed eEF-1γ association with RBP4 promoter. Functionally, si-eEF-1γ reduced cell proliferation and deceased c-Myc and cyclin D1 protein levels. It also suppressed migration, and altered epithelial-mesenchymal transition (EMT) markers, increasing E-cadherin while reducing ZEB1, snail1, vimentin, and N-cadherin levels. Similarly, RBP4 knockdown with siRNA diminished cell proliferation and migration. In vivo, eEF-1γ knockdown in 4T1 xenografts using siRNA led to reduced tumor mass. These findings highlight eEF-1γ as a crucial driver of insulin-induced tumor progression and suggest its potential as a therapeutic target in hepatocellular carcinoma.