APLF的核定位促进乳腺癌转移
Nuclear localization of APLF facilitates breast cancer metastasis
影响因子:4.20000
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
摘要
大多数乳腺癌死亡由转移造成。我们先前报道说，DNA修复因子和组蛋白伴侣APRATAXIN PNK样因子（APLF）参与了EMT相关的三阴性乳腺癌（TNBC）细胞的转移。但是，非转移细胞也表示APLF，疾病进步的含义仍然不确定。在这里，我们证明乳腺癌细胞的转移性预后可以通过APLF的细胞定位确定。使用TNBC患者样品和细胞系，我们发现APLF位于细胞核和细胞质中，而其他亚型的乳腺癌则具有胞质或核周定位。为了研究体外和体内的转移性特性，我们通过在没有假定的APLF NLS的情况下稳定地产生了Luminal Subtype MCF7细胞中的APLF差异定位来建模APLF差异定位。非转移性MCF7细胞中的核APLF表现出明显的迁移，侵袭和转移潜力。我们从分子研究中获得了机械洞察力，即PARP1可以促进APLF从细胞质到细胞核的转运，从而有助于与EMT相关的TNBC细胞的转移。 Olaparib对PARP1酶活性的抑制作用废除了APLF的核表达，而与EMT相关的基因表达丧失。因此，我们的发现表明，APLF的细胞定位可以预测乳腺癌转移的风险，因此可以被利用以确定疾病进展。我们预计抑制胞质PARP1-APLF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.