Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, California, USA.
FASEB J. 2022 Mar;36(3):e22201. doi: 10.1096/fj.202101466R.
Oncogene activation, massive proliferation, and increased nutrient demands often result in nutrient and oxygen deprivation in solid tumors including breast cancer (BC), leading to the induction of oxidative stress and endoplasmic reticulum (ER) stress, and subsequently triggering integrated stress response (ISR). To elucidate the role of long non-coding RNAs (lncRNAs) in the ISR of BC, we performed transcriptome analyses and identified a lncRNA, UBA6-AS1, which was upregulated upon amino acid deprivation and ER stress. UBA6-AS1 was preferentially induced in triple-negative BC (TNBC) cells deprived of arginine or glutamine, two critical amino acids required for cancer cell growth, or treated with ER stress inducers. Mechanistically, UBA6-AS1 was regulated through the GCN2/eIF2α/ATF4 pathway, one of the major routes mediating ISR in amino acid sensing. In addition, both in vitro and in vivo assays indicated that UBA6-AS1 promoted TNBC cell survival when cells encountered metabolic stress, implicating a regulatory role of UBA6-AS1 in response to intratumoral metabolic stress during tumor progression. Moreover, PARP1 expression and activity were positively regulated by the GCN2/UBA6-AS1 axis upon amino acid deprivation. In conclusion, our data suggest that UBA6-AS1 is a novel lncRNA regulating ISR upon metabolic stress induction to promote TNBC cell survival. Furthermore, the GCN2-ATF4 axis is important for UBA6-AS1 induction to enhance PARP1 activity and could serve as a marker for the susceptibility of PARP inhibitors in TNBC.
癌基因激活、大量增殖和营养需求增加，常常导致包括乳腺癌（BC）在内的实体瘤发生营养和氧气剥夺，导致氧化应激和内质网（ER）应激的诱导，进而触发整合应激反应（ISR）。为了阐明长非编码 RNA（lncRNA）在 BC 的 ISR 中的作用，我们进行了转录组分析，鉴定出一种 lncRNA，UBA6-AS1，它在氨基酸剥夺和 ER 应激时上调。UBA6-AS1 在缺乏精氨酸或谷氨酰胺（两种癌细胞生长所必需的关键氨基酸）或用 ER 应激诱导剂处理的三阴性乳腺癌（TNBC）细胞中优先诱导。从机制上讲，UBA6-AS1 通过 GCN2/eIF2α/ATF4 途径调节，该途径是介导氨基酸感应中的 ISR 的主要途径之一。此外，体外和体内实验均表明，当细胞遇到代谢应激时，UBA6-AS1 促进 TNBC 细胞存活，这表明 UBA6-AS1 在肿瘤进展过程中对肿瘤内代谢应激的反应中起调节作用。此外，PARP1 的表达和活性在氨基酸剥夺时受 GCN2/UBA6-AS1 轴的正调控。总之，我们的数据表明，UBA6-AS1 是一种新型 lncRNA，可调节代谢应激诱导下的 ISR，以促进 TNBC 细胞存活。此外，GCN2-ATF4 轴对于 UBA6-AS1 的诱导增强 PARP1 活性非常重要，可作为 TNBC 中 PARP 抑制剂易感性的标志物。
