Anticancer research · 2025
NSUN7 Suppression Reduces Metastatic Potential and Restores Sensitivity to 4-OH Tamoxifen in Resistant MCF-7 Cells.
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Mahmood Sana, Chernov Andrei V, Khan Sehrish, Chitteti Ramamurthy, Salihah Salmma Salamah, Qureshi Sohail A, Patel Hemal H, Gul Asma
Аннотация
BACKGROUND/AIM: Tamoxifen remains a first-line treatment for estrogen receptor-positive breast cancer. Emerging evidence indicates that aberrant 5-methylcytosine (m5C) modification of RNAs contributes to chemotherapeutic resistance in various types of cancer, however their role in determining tamoxifen resistance in breast cancer remains elusive.
MATERIALS AND METHODS: We measured global m5C RNA methylation and expression of its regulating enzymes in tamoxifen-sensitive (MCF-7) versus tamoxifen-resistant cells (MCF-7 Tam1). Expression of the most significantly dysregulated enzyme NOP2/Sun RNA methyltransferase family member 7 (NSUN7), the key m5C writer methyltransferase, was depleted using siRNA-mediated knockdown. Functional assays were performed to measure sensitivity to tamoxifen, cell migration, and colony-forming potential. RNA sequencing followed by enrichment and network analysis identified NSUN7-regulated pathways and hub genes. Finally, the prognostic relevance of hub genes was assessed using the Gene Expression Profiling Interactive Analysis platform.
RESULTS: Tamoxifen-resistant cells exhibited a significant elevation in global m5C levels and expression of NSUN7. siRNA-mediated reduction of NSUN7 significantly restored sensitivity to tamoxifen, reducing the half-maximal inhibitory concentration by ~50%, and significantly inhibited cell migration and colony-forming potential. Transcriptomic profiling and enrichment analysis identified that NSUN7 targets were enriched in crucial pathways, including mitogen-activated protein kinase pathway, phosphatidylinositol signaling, cell cycle, and focal adhesion. Notably, NSUN7 depletion caused dysregulation in the expression of genes implicated in tamoxifen resistance, such as brain acid-soluble protein 1 (BASP1), tissue inhibitor of metalloproteinase 3 (TIMP3), ajuba LIM protein (AJUBA), S-phase kinase-associated protein 2 (SKP2) and yes-associated protein 1 (YAP1). Network analysis further identified NSUN7-regulated hub genes significantly associated with disease prognosis.
CONCLUSION: Our study identified that NSUN7 regulates key oncogenic pathways associated with tamoxifen resistance and metastasis. Its suppression enhanced tamoxifen sensitivity and reduced metastatic potential, collectively highlighting NSUN7 as a novel driver of tamoxifen resistance and a potent therapeutic target in estrogen receptor-positive breast cancer.
MATERIALS AND METHODS: We measured global m5C RNA methylation and expression of its regulating enzymes in tamoxifen-sensitive (MCF-7) versus tamoxifen-resistant cells (MCF-7 Tam1). Expression of the most significantly dysregulated enzyme NOP2/Sun RNA methyltransferase family member 7 (NSUN7), the key m5C writer methyltransferase, was depleted using siRNA-mediated knockdown. Functional assays were performed to measure sensitivity to tamoxifen, cell migration, and colony-forming potential. RNA sequencing followed by enrichment and network analysis identified NSUN7-regulated pathways and hub genes. Finally, the prognostic relevance of hub genes was assessed using the Gene Expression Profiling Interactive Analysis platform.
RESULTS: Tamoxifen-resistant cells exhibited a significant elevation in global m5C levels and expression of NSUN7. siRNA-mediated reduction of NSUN7 significantly restored sensitivity to tamoxifen, reducing the half-maximal inhibitory concentration by ~50%, and significantly inhibited cell migration and colony-forming potential. Transcriptomic profiling and enrichment analysis identified that NSUN7 targets were enriched in crucial pathways, including mitogen-activated protein kinase pathway, phosphatidylinositol signaling, cell cycle, and focal adhesion. Notably, NSUN7 depletion caused dysregulation in the expression of genes implicated in tamoxifen resistance, such as brain acid-soluble protein 1 (BASP1), tissue inhibitor of metalloproteinase 3 (TIMP3), ajuba LIM protein (AJUBA), S-phase kinase-associated protein 2 (SKP2) and yes-associated protein 1 (YAP1). Network analysis further identified NSUN7-regulated hub genes significantly associated with disease prognosis.
CONCLUSION: Our study identified that NSUN7 regulates key oncogenic pathways associated with tamoxifen resistance and metastasis. Its suppression enhanced tamoxifen sensitivity and reduced metastatic potential, collectively highlighting NSUN7 as a novel driver of tamoxifen resistance and a potent therapeutic target in estrogen receptor-positive breast cancer.