APLF的核定位促进乳腺癌转移

Nuclear localization of APLF facilitates breast cancer metastasis

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BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

影响因子:4.2

分区:生物学2区 / 生物物理2区生化与分子生物学3区

发表日期:2025 Jan

作者: Debparna Nandy, Mayur Balkrishna Shirude, Archana S, Anjali Devarajan, Ananda Mukherjee, Debasree Dutta

DOI: 10.1016/j.bbadis.2024.167537

摘要

大多数乳腺癌死亡源于转移。我们之前报道DNA修复因子和组蛋白伴侣蛋白Aprataxin PNK样因子（APLF）参与三阴性乳腺癌（TNBC）细胞的上皮-间质转化（EMT）相关转移。然而，非转移性细胞也表达APLF，其在疾病进展中的意义尚不明确。本研究显示乳腺癌细胞的转移预后可能由APLF的细胞定位决定。利用TNBC患者样本和细胞系，我们发现APLF在细胞核和细胞质中均有定位，而其他亚型乳腺癌则多为细胞质或核周定位。为了研究体内外的转移特性，我们通过稳定表达带有核定位信号（NLS）的APLF标记，在非转移性乳腺癌细胞系MCF7中模拟APLF的不同定位（缺乏APLF NLS）。核定位的APLF增强了MCF7细胞的迁移、侵袭和转移潜力。分子机制研究显示，PARP1可能促使APLF从细胞质转运到细胞核，从而促进与EMT相关的TNBC细胞转移。用奥拉帕尼（olaparib）抑制PARP1酶活性，导致APLF核表达下降，并伴随EMT相关基因表达的下降。因此，我们的研究表明APLF的细胞定位可能预测乳腺癌的转移风险，亦可作为疾病进展的标志。我们预期，抑制细胞质PARP1与APLF的相互作用可能有助于预防TNBC患者的乳腺癌转移。

Abstract

Most breast cancer deaths result from metastases. We previously reported that DNA repair factor and histone chaperone Aprataxin PNK-like Factor (APLF) is involved in EMT-associated metastasis of triple negative breast cancer (TNBC) cells. However, non-metastatic cells also expressed APLF, the implications of which in disease advancement remain uncertain. Here, we demonstrate that the metastatic prognosis of breast cancer cells may be determined by the cellular localization of APLF. Using TNBC patient samples and cell lines, we discovered that APLF was localized in the nucleus and cytoplasm, whereas other subtypes of breast cancer had cytosolic or perinuclear localization. To investigate metastatic properties in vitro and in vivo, we modeled APLF differential localization by stably producing APLF-tagged nuclear localization signal (NLS) in the luminal subtype MCF7 cells in the absence of putative APLF NLS. Nuclear APLF in non-metastatic MCF7 cells demonstrated pronounced migration, invasion and metastatic potential. We obtained the mechanistic insight from molecular studies that PARP1 could facilitate the transport of APLF from the cytosol to the nucleus, assisting in the metastasis of TNBC cells linked with EMT. Inhibition of PARP1 enzymatic activity with olaparib abrogated the nuclear expression of APLF with loss in expression of genes associated with EMT. Thus, our findings reveal that cellular localization of APLF may predict the risk of breast cancer to metastasize and hence could be exploited to determine the disease progression. We anticipate that the inhibition of cytosolic PARP1-APLF interaction may potentially aid in the prevention of breast cancer metastasis in TNBC patients.