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<p>Cancer stem cells (CSCs) play a critical role in tumor initiation, progression, and recurrence. How liver CSCs initiate their self-renewal remains elusive. Here we identify a conserved small nucleolar RNA (snoRNA), <i>SNORA49</i>, which is lowly expressed in liver CSCs, as a negative regulator of CSC self-renewal. <i>SNORA49</i> knockout enhances the self-renewal capacity of liver CSCs and accelerates hepatocellular carcinoma (HCC) tumorigenesis, whereas overexpression of <i>SNORA49</i> suppresses tumor formation. Mechanistically, in non-CSCs, <i>SNORA49</i> is specifically localized in the nucleoplasm to associate with HNRNPU, blocking its interaction with ZC3H18, resulting in inhibition of SOX9 transcription. In liver CSCs, lowly expressed <i>SNORA49</i> releases HNRNPU to engage with ZC3H18 and enrich on the promoter of SOX9, leading to its transcription. Of note, lipid nanoparticle (LNP)-mediated delivery of <i>SNORA49</i> RNAs and antisense oligonucleotides (ASOs) targeting <i>SOX9</i> exerts potent synergistic anti-tumor effect on HCC tumors. Our findings define <i>SNORA49</i> as a tumor suppressor in liver CSCs, and restoring <i>SNORA49</i> levels and silencing <i>SOX9</i> with LNP-delivered system may provide therapeutic strategy for clinical intervention to HCC patients.</p>

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SNORA49 negatively regulates self-renewal of liver cancer stem cells and hepatocarcinogenesis via suppressing SOX9 transcription

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月21日

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  • Zhibin Yi,
  • Ziheng Zhou,
  • Yang Gu,
  • Yuwei Xu,
  • Ziqi Xiao,
  • Zhen Xiong,
  • Jianyi Wang,
  • Hui Guo,
  • Ying Du,
  • Yun Chen,
  • Zusen Fan

摘要

Cancer stem cells (CSCs) play a critical role in tumor initiation, progression, and recurrence. How liver CSCs initiate their self-renewal remains elusive. Here we identify a conserved small nucleolar RNA (snoRNA), SNORA49, which is lowly expressed in liver CSCs, as a negative regulator of CSC self-renewal. SNORA49 knockout enhances the self-renewal capacity of liver CSCs and accelerates hepatocellular carcinoma (HCC) tumorigenesis, whereas overexpression of SNORA49 suppresses tumor formation. Mechanistically, in non-CSCs, SNORA49 is specifically localized in the nucleoplasm to associate with HNRNPU, blocking its interaction with ZC3H18, resulting in inhibition of SOX9 transcription. In liver CSCs, lowly expressed SNORA49 releases HNRNPU to engage with ZC3H18 and enrich on the promoter of SOX9, leading to its transcription. Of note, lipid nanoparticle (LNP)-mediated delivery of SNORA49 RNAs and antisense oligonucleotides (ASOs) targeting SOX9 exerts potent synergistic anti-tumor effect on HCC tumors. Our findings define SNORA49 as a tumor suppressor in liver CSCs, and restoring SNORA49 levels and silencing SOX9 with LNP-delivered system may provide therapeutic strategy for clinical intervention to HCC patients.