Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125 Turin, Regione Gonzole 10, 10043, Orbassano, Turin, Italy.
Department of Oncology, University of Turin, Via Michelangelo 27, 10125, Turin, Italy.
Free Radic Biol Med. 2019 Sep;141:205-219. doi: 10.1016/j.freeradbiomed.2019.06.009. Epub 2019 Jun 15.
The transcriptional regulator YAP plays an important role in cancer progression and is negatively controlled by the Hippo pathway. YAP is frequently overexpressed in human cancers, including bladder cancer. Interestingly, YAP expression and activity can be inhibited by pro-oxidant conditions; moreover, YAP itself can also affect the cellular redox status through multiple mechanisms. 4-Hydroxynonenal (HNE), the most intensively studied end product of lipid peroxidation, is a pro-oxidant agent able to deplete GSH and has an anti-tumoral effect by affecting multiple signal pathways, including the down-regulation of oncogene expressions. These observations prompted us to investigate the effect of HNE on YAP expression and activity. We demonstrated that HNE inhibited YAP expression and its target genes in bladder cancer cells through a redox-dependent mechanism. Moreover, the YAP down-regulation was accompanied by an inhibition of proliferation, migration, invasion, and angiogenesis, as well as by an accumulation of cells in the G2/M phase of cell cycle and by an induction of apoptosis. We also established the YAP role in inhibiting cell viability and inducing apoptosis in HNE-treated cells by using an expression vector for YAP. Furthermore, we identified a post-translational mechanism for the HNE-induced YAP expression inhibition, involving an increase of YAP phosphorylation and ubiquitination, leading to proteasomal degradation. Our data established that HNE can post-translationally down-regulate YAP through a redox-dependent mechanism and that this modulation can contribute to determining the specific anti-cancer effects of HNE.
转录调节因子 YAP 在癌症进展中发挥重要作用，并且受到 Hippo 通路的负调控。YAP 在包括膀胱癌在内的人类癌症中经常过表达。有趣的是，YAP 的表达和活性可以被促氧化剂条件抑制；此外，YAP 本身也可以通过多种机制影响细胞的氧化还原状态。4-羟基壬烯醛（HNE）是脂质过氧化作用最深入研究的终产物之一，是一种促氧化剂，能够耗竭 GSH，并通过影响多种信号通路，包括下调癌基因表达，具有抗肿瘤作用。这些观察结果促使我们研究 HNE 对 YAP 表达和活性的影响。我们证明，HNE 通过一种依赖于氧化还原的机制抑制膀胱癌细胞中的 YAP 表达及其靶基因。此外，YAP 的下调伴随着增殖、迁移、侵袭和血管生成的抑制，以及细胞在细胞周期的 G2/M 期的积累和凋亡的诱导。我们还通过 YAP 表达载体的使用，确定了 YAP 在 HNE 处理细胞中抑制细胞活力和诱导凋亡中的作用。此外，我们确定了 HNE 诱导的 YAP 表达抑制的一种翻译后机制，涉及 YAP 磷酸化和泛素化增加，导致蛋白酶体降解。我们的数据表明，HNE 可以通过依赖于氧化还原的机制对 YAP 进行翻译后下调，并且这种调节可能有助于确定 HNE 的特定抗癌作用。
