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<p>Histone post-translational modifications are intimately linked to human diseases, including cancers. While diverse regulatory mechanisms have been described, how long non-coding RNAs (lncRNAs) control histone acetylation remains incompletely understood. Here, integrative bioinformatics analysis implicates the lncRNA HITT (HIF-1α inhibitor at the translation level) in histone modification-related pathways. Mechanistically, HITT selectively suppresses H3/H4 acetylation in colorectal cancer cells. Using siRNA-based loss-of-function screening and pharmacological inhibition, we identify the sirtuin deacetylase SIRT6 as an essential mediator of this effect. HITT directly binds SIRT6 and increases SIRT6 protein abundance by attenuating its association with the E3 ubiquitin ligase mouse double minute 2 homolog (MDM2), thereby reducing MDM2-dependent ubiquitination and proteasomal turnover of SIRT6. Conversely, the SIRT6 agonist MDL-800 upregulates the transcription factor E2F1, thereby promoting E2F1-dependent transcription of HITT. Functionally, increased HITT expression cooperates with MDL-800 to inhibit colorectal cancer cell proliferation in vitro and suppress tumor growth in vivo. Collectively, these findings define a feed-forward HITT-SIRT6 axis that stabilizes SIRT6 and constrains histone H3/H4 acetylation homeostasis, highlighting a potential combination strategy for colorectal cancer therapy.</p>

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LncRNA HITT stabilizes SIRT6 to restrain H3/H4 acetylation and suppress colorectal cancer growth

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月27日

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  • Bolun Li,
  • Zhiyuan Xiang,
  • Hao Liu,
  • Qiannan Cheng,
  • Haoyu Wang,
  • Kaiting Chen,
  • Jing Hu,
  • Ying Hu

摘要

Histone post-translational modifications are intimately linked to human diseases, including cancers. While diverse regulatory mechanisms have been described, how long non-coding RNAs (lncRNAs) control histone acetylation remains incompletely understood. Here, integrative bioinformatics analysis implicates the lncRNA HITT (HIF-1α inhibitor at the translation level) in histone modification-related pathways. Mechanistically, HITT selectively suppresses H3/H4 acetylation in colorectal cancer cells. Using siRNA-based loss-of-function screening and pharmacological inhibition, we identify the sirtuin deacetylase SIRT6 as an essential mediator of this effect. HITT directly binds SIRT6 and increases SIRT6 protein abundance by attenuating its association with the E3 ubiquitin ligase mouse double minute 2 homolog (MDM2), thereby reducing MDM2-dependent ubiquitination and proteasomal turnover of SIRT6. Conversely, the SIRT6 agonist MDL-800 upregulates the transcription factor E2F1, thereby promoting E2F1-dependent transcription of HITT. Functionally, increased HITT expression cooperates with MDL-800 to inhibit colorectal cancer cell proliferation in vitro and suppress tumor growth in vivo. Collectively, these findings define a feed-forward HITT-SIRT6 axis that stabilizes SIRT6 and constrains histone H3/H4 acetylation homeostasis, highlighting a potential combination strategy for colorectal cancer therapy.