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Background <p>X-inactive specific transcript (Xist), a long non-coding RNA and MacroH2A1, a histone variant are primarily involved in maintaining the inactive X chromosome in females. Xist downregulation was correlated with augmented cancer cell invasion, migration, cancer stemness and the reactivation of certain X-linked genes in ovarian cancer. Nicotinamide N-methyltransferase (NNMT) is increasingly associated with tumor progression and cancer stem cell enrichment as well as epithelial-mesenchymal transition (EMT). However, a potential relationship between NNMT and Xist, MacroH2A1 alongside stem cell mediating transcription factors (NANOG, Oct4, SOX2) and the EMT marker SNAI1 has not been previously explored.</p> Methods <p>OVCAR-3 and SKOV-3 ovarian cancer cell lines were treated with NNMT siRNA or the NNMT inhibitor JBSNF-000088. Expression of Xist, NANOG, Oct4, SOX2, SNAI1, MacroH2A1 and NNMT were analyzed via RT qPCR and Western Blotting. Invasion and migration assays were performed using the xCELLigence RTCA system. Database analyses assessed Xist expression, survival and methylation correlations.</p> Results <p>NNMT silencing significantly increased Xist and MacroH2A1 expression, while decreasing NANOG, Oct4, SOX2, and SNAI1 (<i>p</i> &lt; 0.05). NNMT silencing decreased invasion and migration capabilities of cancer cells (<i>p</i> &lt; 0.001).</p> Conclusion <p>These findings suggest a potential link between NNMT expression, cancer stemness, and Xist regulation in ovarian cancer cell lines. Upregulation of Xist and decrease in the levels of stemness and EMT factors following NNMT silencing may be associated with a more favorable molecular profile. The concurrent increase in MacroH2A1 expression supports the potential role of NNMT in modulating X chromosome reactivation in ovarian cancer possibly through the repressive effects of pluripotency factors on Xist.</p>

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Nicotinamide N-methyltransferase gene silencing is associated with upregulation of X-inactive specific transcript and downregulation of stemness-related transcription factors in ovarian cancer

  • 期刊论文

  • 发表日期：

    2026年1月9日

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  • Serra Akar İnan,
  • Ebru Alimogullari,
  • Raziye Toksöz,
  • Oğuz Arı,
  • Sevil Çaylı

摘要

Background

X-inactive specific transcript (Xist), a long non-coding RNA and MacroH2A1, a histone variant are primarily involved in maintaining the inactive X chromosome in females. Xist downregulation was correlated with augmented cancer cell invasion, migration, cancer stemness and the reactivation of certain X-linked genes in ovarian cancer. Nicotinamide N-methyltransferase (NNMT) is increasingly associated with tumor progression and cancer stem cell enrichment as well as epithelial-mesenchymal transition (EMT). However, a potential relationship between NNMT and Xist, MacroH2A1 alongside stem cell mediating transcription factors (NANOG, Oct4, SOX2) and the EMT marker SNAI1 has not been previously explored.

Methods

OVCAR-3 and SKOV-3 ovarian cancer cell lines were treated with NNMT siRNA or the NNMT inhibitor JBSNF-000088. Expression of Xist, NANOG, Oct4, SOX2, SNAI1, MacroH2A1 and NNMT were analyzed via RT qPCR and Western Blotting. Invasion and migration assays were performed using the xCELLigence RTCA system. Database analyses assessed Xist expression, survival and methylation correlations.

Results

NNMT silencing significantly increased Xist and MacroH2A1 expression, while decreasing NANOG, Oct4, SOX2, and SNAI1 (p < 0.05). NNMT silencing decreased invasion and migration capabilities of cancer cells (p < 0.001).

Conclusion

These findings suggest a potential link between NNMT expression, cancer stemness, and Xist regulation in ovarian cancer cell lines. Upregulation of Xist and decrease in the levels of stemness and EMT factors following NNMT silencing may be associated with a more favorable molecular profile. The concurrent increase in MacroH2A1 expression supports the potential role of NNMT in modulating X chromosome reactivation in ovarian cancer possibly through the repressive effects of pluripotency factors on Xist.