Tsoi Ho, You Chan-Ping, Cheung Koei Ho-Lam, Tse Yin-Suen, Khoo Ui-Soon
Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Int J Mol Sci. 2025 May 22;26(11):4989. doi: 10.3390/ijms26114989.
BQ323636.1 (BQ), a splice variant of NCOR2, is associated with endocrine therapy resistance and poorer prognosis in ER-positive breast cancer. This study investigates the role of BQ in modulating lipid metabolism to support tumor growth. RNA sequencing of BQ-overexpressing breast cancer cells revealed significant enrichment of fatty acid metabolism pathways (hsa01212 and hsa00061; < 0.05), with ACSL4 identified as a key target. We show that BQ disrupts the NCOR2-PPARγ interaction, leading to ACSL4 upregulation, which enhances fatty acid oxidation (FAO), acetyl-CoA by 1.8-fold, and ATP production by 2.5-fold to fuel tumor proliferation. BQ also upregulates FASN and SCD, increasing lipids. A metabolites study with mass spectrometry indicated that BQ overexpression increases the fatty acid amount from 47.97 nmol/10 cells to 75.18 nmol/10 cells in MCF7 and from 56.19 nmol/10 cells to 95.37 nmol/10 cells in ZR-75. BQ activates NRF2, which mitigates ROS-induced stress, promoting cell survival. Targeting ACSL4 with the inhibitor PRGL493 reduced ATP production and suppressed tumor growth in vitro and in vivo, without inducing apoptosis, suggesting a cytostatic effect. PRGL493 treatment can reduce BQ overexpressing tumors by 40% in the xenograft model. These results highlight BQ can serve as a transcriptional hub driving lipid metabolism via ACSL4 in breast cancer. Our findings suggest that ACSL4 inhibition could be a novel therapeutic strategy to overcome treatment resistance in high-BQ expressing ER-positive breast cancer.
BQ323636.1（BQ）是NCOR2的一种剪接变体，与雌激素受体（ER）阳性乳腺癌的内分泌治疗耐药性及较差的预后相关。本研究调查了BQ在调节脂质代谢以支持肿瘤生长中的作用。对过表达BQ的乳腺癌细胞进行RNA测序发现，脂肪酸代谢途径（hsa01212和hsa00061；P<0.05）显著富集，其中ACSL4被确定为关键靶点。我们发现，BQ破坏了NCOR2与过氧化物酶体增殖物激活受体γ（PPARγ）的相互作用，导致ACSL4上调，从而增强脂肪酸氧化（FAO），使乙酰辅酶A增加1.8倍，三磷酸腺苷（ATP）生成增加2.5倍，为肿瘤增殖提供能量。BQ还上调脂肪酸合酶（FASN）和硬脂酰辅酶A去饱和酶（SCD），增加脂质。一项质谱代谢物研究表明，过表达BQ可使MCF7细胞中脂肪酸量从47.97 nmol/10个细胞增加到75.18 nmol/10个细胞，使ZR-75细胞中脂肪酸量从56.19 nmol/10个细胞增加到95.37 nmol/10个细胞。BQ激活核因子E2相关因子2（NRF2），减轻活性氧（ROS）诱导的应激，促进细胞存活。用抑制剂PRGL493靶向ACSL4可降低ATP生成，并在体外和体内抑制肿瘤生长，且不诱导细胞凋亡，提示其具有细胞生长抑制作用。在异种移植模型中，PRGL493治疗可使过表达BQ的肿瘤缩小40%。这些结果表明，BQ可作为一个转录枢纽，通过ACSL4驱动乳腺癌中的脂质代谢。我们的研究结果表明，抑制ACSL4可能是克服高表达BQ的ER阳性乳腺癌治疗耐药性的一种新的治疗策略。
