NSUN7 Suppression Reduces Metastatic Potential and Restores Sensitivity to 4-OH Tamoxifen in Resistant MCF-7 Cells - PubMed (original) (raw)

NSUN7 Suppression Reduces Metastatic Potential and Restores Sensitivity to 4-OH Tamoxifen in Resistant MCF-7 Cells

Sana Mahmood et al. Anticancer Res. 2025 Dec.

Abstract

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.

Keywords: MCF-7; NSUN7; Tamoxifen; breast cancer; drug resistance; methyl cytosine.

Copyright © 2025 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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