Dataset Information

Long noncoding RNA LINC00239 inhibits ferroptosis in colorectal cancer by binding to Keap1 to stabilize Nrf2.

ABSTRACT: Ferroptosis, a novel regulated cell death induced by iron-dependent lipid peroxidation, plays an important role in tumor development and drug resistance. Long noncoding RNAs (lncRNAs) are associated with various types of cancer. However, the precise roles of many lncRNAs in tumorigenesis remain elusive. Here we explored the transcriptomic profiles of lncRNAs in primary CRC tissues and corresponding paired adjacent non-tumor tissues by RNA-seq and found that LINC00239 was significantly overexpressed in colorectal cancer tissues. Abnormally high expression of LINC00239 predicts poorer survival and prognosis in colorectal cancer patients. Concurrently, we elucidated the role of LINC00239 as a tumor-promoting factor in CRC through in vitro functional studies and in vivo tumor xenograft models. Importantly, overexpression of LINC00239 decreased the anti-tumor activity of erastin and RSL3 by inhibiting ferroptosis. Collectively, these data suggest that LINC00239 plays a novel and indispensable role in ferroptosis by nucleotides 1-315 of LINC00239 to interact with the Kelch domain (Nrf2-binding site) of Keap1, inhibiting Nrf2 ubiquitination and increasing Nrf2 protein stability. Considering the recurrence and chemoresistance constitute the leading cause of death in colorectal cancer (CRC), ferroptosis induction may be a promising therapeutic strategy for CRC patients with low LINC00239 expression.

SUBMITTER: Han Y

PROVIDER: S-EPMC9424287 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Long noncoding RNA LINC00239 inhibits ferroptosis in colorectal cancer by binding to Keap1 to stabilize Nrf2.

Han Yuying Y Gao Xiaoliang X Wu Nan N Jin Yirong Y Zhou He H Wang Weijie W Liu Hao H Chu Yi Y Cao Jiayi J Jiang Mingzuo M Yang Suzhen S Shi Yanting Y Xie Xin X Chen Fulin F Han Ying Y Qin Wen W Xu Bing B Liang Jie J

Cell death & disease 20220829 8

Ferroptosis, a novel regulated cell death induced by iron-dependent lipid peroxidation, plays an important role in tumor development and drug resistance. Long noncoding RNAs (lncRNAs) are associated with various types of cancer. However, the precise roles of many lncRNAs in tumorigenesis remain elusive. Here we explored the transcriptomic profiles of lncRNAs in primary CRC tissues and corresponding paired adjacent non-tumor tissues by RNA-seq and found that LINC00239 was significantly overexpres ...[more]

PMID: 36038548

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Project description:BackgroundPancreatic 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.MethodsA 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.ResultsLINC00578 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.ConclusionsThis 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.

Dataset Information

Long noncoding RNA LINC00239 inhibits ferroptosis in colorectal cancer by binding to Keap1 to stabilize Nrf2.

Publications

Long noncoding RNA LINC00239 inhibits ferroptosis in colorectal cancer by binding to Keap1 to stabilize Nrf2.

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