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<p>Lung adenocarcinoma (LUAD) is the major histological subtype of non-small cell lung cancer (NSCLC). The mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of anabolic growth and metabolism, has been implicated in unfavorable prognosis and therapeutic resistance in LUAD. Nevertheless, how this association is mechanistically established remains insufficiently understood. Here, by integrating TCGA/GEO datasets with our institutional LUAD single-cell RNA-seq, we identified the atypical E2F factor E2F8 as the member most closely associated with the mTORC1 pathway and found that E2F8 is upregulated in LUAD and that higher E2F8 levels correlate with adverse clinicopathological features and poorer prognosis. In PC-9 and H1975 cells, E2F8 overexpression enhanced proliferation, clonogenicity, migration, and xenograft growth, whereas E2F8 silencing produced the opposite effects; rapamycin partially reversed these phenotypes, indicating mTORC1 dependence. Mechanistically, E2F8 activated transcription of the HECT-type E3 ligase WWP1, which recognized PPxY-containing TSC1 and mediated K48-linked polyubiquitination at K662, promoting proteasomal degradation of TSC1 and sustaining mTORC1 signaling, as evidenced by increased <i>p</i>-mTOR (Ser2448), <i>p</i>-S6K1, and <i>p</i>-4EBP1. WWP1 knockdown markedly blunted E2F8-induced mTORC1 activation, preserved TSC1 abundance, and attenuated downstream mTORC1 readouts under E2F8/WWP1 activation, supporting TSC1 as the critical substrate. Pharmacologic WWP1 inhibition with indole-3-carbinol (I3C) restored TSC1, reduced <i>p</i>-mTOR (Ser2448), and suppressed LUAD xenograft growth, defining an E2F8-WWP1-TSC1-mTORC1 axis as a targetable circuit in LUAD.</p>

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E2F-mediated activation of mTORC1 through the ubiquitin-proteasome system promotes lung adenocarcinoma progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月19日

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  • Wentao Xue,
  • Mengen Wang,
  • Tong Hu,
  • Shina Guo,
  • Anchi Hu,
  • Yan Gu,
  • Hongchang Wang,
  • Guang Mu,
  • Wenhao Zhang,
  • Chenghao Fu,
  • Zizhang Guo,
  • Ke Wei,
  • Yanan Li,
  • Jun Wang

摘要

Lung adenocarcinoma (LUAD) is the major histological subtype of non-small cell lung cancer (NSCLC). The mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of anabolic growth and metabolism, has been implicated in unfavorable prognosis and therapeutic resistance in LUAD. Nevertheless, how this association is mechanistically established remains insufficiently understood. Here, by integrating TCGA/GEO datasets with our institutional LUAD single-cell RNA-seq, we identified the atypical E2F factor E2F8 as the member most closely associated with the mTORC1 pathway and found that E2F8 is upregulated in LUAD and that higher E2F8 levels correlate with adverse clinicopathological features and poorer prognosis. In PC-9 and H1975 cells, E2F8 overexpression enhanced proliferation, clonogenicity, migration, and xenograft growth, whereas E2F8 silencing produced the opposite effects; rapamycin partially reversed these phenotypes, indicating mTORC1 dependence. Mechanistically, E2F8 activated transcription of the HECT-type E3 ligase WWP1, which recognized PPxY-containing TSC1 and mediated K48-linked polyubiquitination at K662, promoting proteasomal degradation of TSC1 and sustaining mTORC1 signaling, as evidenced by increased p-mTOR (Ser2448), p-S6K1, and p-4EBP1. WWP1 knockdown markedly blunted E2F8-induced mTORC1 activation, preserved TSC1 abundance, and attenuated downstream mTORC1 readouts under E2F8/WWP1 activation, supporting TSC1 as the critical substrate. Pharmacologic WWP1 inhibition with indole-3-carbinol (I3C) restored TSC1, reduced p-mTOR (Ser2448), and suppressed LUAD xenograft growth, defining an E2F8-WWP1-TSC1-mTORC1 axis as a targetable circuit in LUAD.