Long Noncoding RNA LINC00578 Inhibits Ferroptosis in Pancreatic Cancer via Regulating SLC7A11 Ubiquitination

Abstract

Background. Pancreatic cancer is a highly aggressive malignancy worldwide with rapid development and an exceedingly poor prognosis. lncRNAs play crucial roles in regulating the biological behaviors of tumor cells. In this study, we discovered that LINC00578 acted as a regulator of ferroptosis in pancreatic cancer. Methods. A series of loss- and gain-of-function experiments in vitro and in vivo were performed to explore the oncogenic role of LINC00578 in pancreatic cancer development and progression. Label-free proteomic analysis was performed to select LINC00578-related differentially expressed proteins. Pull-down and RNA immunoprecipitation assays were carried out to determine and validate the binding protein of LINC00578. Coimmunoprecipitation assays were used to investigate the association of LINC00578 with SLC7A11 in ubiquitination and to confirm the interaction between ubiquitin-conjugating enzyme E2 K (UBE2K) and SLC7A11. An immunohistochemical assay was used to confirm the correlation between LINC00578 and SLC7A11 in the clinic. Results. LINC00578 positively regulated cell proliferation and invasion in vitro and tumorigenesis in vivo in pancreatic cancer. LINC00578 can obviously inhibit ferroptosis events, including cell proliferation, reactive oxygen species (ROS) generation, and mitochondrial membrane potential (MMP) depolarization. In addition, the LINC00578-induced inhibitory effect on ferroptosis events was rescued by SLC7A11 knockdown. Mechanistically, LINC00578 directly binds UBE2K to decrease the ubiquitination of SLC7A11, thus accelerating SLC7A11 expression. In the clinic, LINC00578 is closely associated with clinicopathologic factors and poor prognosis and correlated with SLC7A11 expression in pancreatic cancer. Conclusions. This study elucidated that LINC00578 acts as an oncogene to promote pancreatic cancer cell progression and suppress ferroptosis by directly combining with UBE2K to inhibit the ubiquitination of SLC7A11, which provides a promising option for the diagnosis and treatment of pancreatic cancer.

Investigating Combined Hypoxia and Stemness Indices for Prognostic Transcripts in Gastric Cancer: Machine Learning and Network Analysis Approaches

“…GLRB is also considered as a potential drug target for colorectal cancer (64). LINC00578, a recently identified long noncoding RNA (lncRNA), has been linked to prognosis in lung, breast, and pancreatic cancers (65)(66)(67). Furthermore, research suggests that LINC00578 promotes the development and growth of pancreatic cancer by inhibiting ferroptosis, a type of cell death induced by iron-dependent oxidation (67).…”

“…LINC00578, a recently identified long noncoding RNA (lncRNA), has been linked to prognosis in lung, breast, and pancreatic cancers (65)(66)(67). Furthermore, research suggests that LINC00578 promotes the development and growth of pancreatic cancer by inhibiting ferroptosis, a type of cell death induced by iron-dependent oxidation (67). Long intergenic non-protein coding RNA 968 (LINC00968) may function as an oncogene in certain cancers, such as osteosarcoma (68), while acting as a tumor suppressor in others, such as lung adenocarcinoma (69).…”

Protein modification and degradation in ferroptosis

“…Conversely, the deubiquitinating enzymes OTUB1 and ubiquitin specific peptidase 20 (USP20) mediate the deubiquitination of SLC7A11, thereby stabilizing SLC7A11 levels in cancer cells [ 6 , 122 ]. Additionally, hepatocellular carcinoma ferroptosis associative lncRNA (HEPFAL) accelerates ferroptosis in hepatocellular carcinoma cells, whereas lncRNA LINC00578 inhibits ferroptosis by modulating the ubiquitination of SLC7A11 in pancreatic cancer cells [ 123 , 124 ]. In contrast, fascin actin-bundling protein 1 (FSCN1) directly interacts with SLC7A11, enhancing its degradation by UPS in breast cancer cells [ 125 ].…”

The Regulation of Ferroptosis by Noncoding RNAs

“…Moreover, lncHEPFAL reduces SLC7A11 by promoting its ubiquitination and degradation, eventually enhancing erastin-induced ferroptosis in hepatocellular carcinoma [155]. On the other hand, lncRNA LINC00578 also inhibits SLC7A11 ubiquitination by binding to UBE2K to inhibit ferroptosis in pancreatic cancer [262]. CircBGN directly binds to OTUB1 and SLC7A11, enhancing OTUB1-mediated SLC7A11 deubiquitination to inhibit ferroptosis in breast cancer [263].…”