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Background <p>Hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. UBC9, the sole E2 conjugating enzyme in the SUMOylation pathway, is frequently overexpressed in HCC, yet its specific role in hepatocarcinogenesis remains unclear. This study aims to elucidate the regulatory mechanism of UBC9 in HCC, specifically focusing on its crosstalk with Lamin A (LMNA) via SUMOylation and ubiquitination.</p> Methods <p>We analyzed UBC9 and LMNA expression in HCC tissues using TCGA and GEO datasets and evaluated their correlation with clinical outcomes. A doxycycline-inducible shRNA system was established in Hep3B and Huh-7 cell lines to assess the effects of UBC9 knockdown on cell proliferation, migration, and invasion. Proteomics and ubiquitin-proteomics analyses were performed to identify downstream targets. Mechanisms of LMNA regulation were investigated using immunoprecipitation, site-directed mutagenesis (K144R), and cycloheximide chase assays. Xenograft mouse models were used to validate findings in vivo.</p> Results <p>UBC9 was significantly upregulated in HCC tissues, and high levels correlated with poor prognosis. Knockdown of UBC9 suppressed HCC cell proliferation, migration, and invasion in vitro and tumor growth in vivo. Proteomic screening identified LMNA as a key downstream target. UBC9 depletion led to reduced LMNA protein stability via increased ubiquitination without affecting its mRNA levels. We identified Lysine 144 (K144) as a novel ubiquitination site on LMNA; the K144R mutation or enhanced SUMOylation prevented LMNA degradation. Rescue experiments demonstrated that LMNA knockdown partially reversed the oncogenic phenotype induced by UBC9 overexpression.</p> Conclusions <p>UBC9 promotes HCC progression by stabilizing LMNA through SUMOylation, which prevents ubiquitin-mediated degradation at the K144 site. The UBC9-LMNA axis represents a critical regulatory mechanism and a promising therapeutic target for hepatocellular carcinoma.</p>

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UBC9-mediated regulation of K144 ubiquitination of Lamin A and its implications for hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月22日

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  • QingShui Wang,
  • Ziqiang Liao,
  • Hao Zhang,
  • Ziyi Jin,
  • Zhuoqin Zhong,
  • Xinji Gao,
  • YiMin Huang,
  • Menghua Qiu,
  • Wudan Ren,
  • Yunjia Liu,
  • Liyan Zhang,
  • Runjing Fan,
  • Yaqian Feng,
  • Kunmu Zhang,
  • Yehuda G. Assaraf,
  • Yao Lin

摘要

Background

Hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. UBC9, the sole E2 conjugating enzyme in the SUMOylation pathway, is frequently overexpressed in HCC, yet its specific role in hepatocarcinogenesis remains unclear. This study aims to elucidate the regulatory mechanism of UBC9 in HCC, specifically focusing on its crosstalk with Lamin A (LMNA) via SUMOylation and ubiquitination.

Methods

We analyzed UBC9 and LMNA expression in HCC tissues using TCGA and GEO datasets and evaluated their correlation with clinical outcomes. A doxycycline-inducible shRNA system was established in Hep3B and Huh-7 cell lines to assess the effects of UBC9 knockdown on cell proliferation, migration, and invasion. Proteomics and ubiquitin-proteomics analyses were performed to identify downstream targets. Mechanisms of LMNA regulation were investigated using immunoprecipitation, site-directed mutagenesis (K144R), and cycloheximide chase assays. Xenograft mouse models were used to validate findings in vivo.

Results

UBC9 was significantly upregulated in HCC tissues, and high levels correlated with poor prognosis. Knockdown of UBC9 suppressed HCC cell proliferation, migration, and invasion in vitro and tumor growth in vivo. Proteomic screening identified LMNA as a key downstream target. UBC9 depletion led to reduced LMNA protein stability via increased ubiquitination without affecting its mRNA levels. We identified Lysine 144 (K144) as a novel ubiquitination site on LMNA; the K144R mutation or enhanced SUMOylation prevented LMNA degradation. Rescue experiments demonstrated that LMNA knockdown partially reversed the oncogenic phenotype induced by UBC9 overexpression.

Conclusions

UBC9 promotes HCC progression by stabilizing LMNA through SUMOylation, which prevents ubiquitin-mediated degradation at the K144 site. The UBC9-LMNA axis represents a critical regulatory mechanism and a promising therapeutic target for hepatocellular carcinoma.