LncRNA CDKN2B-AS1 stabilized by IGF2BP3 drives the malignancy of renal clear cell carcinoma through epigenetically activating NUF2 transcription

Abstract

Because of the lack of sensitivity to radiotherapy and chemotherapy, therapeutic options for renal clear cell carcinoma (KIRC) are scarce. Long noncoding RNAs (lncRNAs) play crucial roles in the progression of cancer. However, their functional roles and upstream mechanisms in KIRC remain largely unknown. Exploring the functions of potential essential lncRNAs may lead to the discovery of novel targets for the diagnosis and treatment of KIRC. Here, according to the integrated analysis of RNA sequencing and survival data in TCGA-KIRC datasets, cyclin-dependent kinase inhibitor 2B antisense lncRNA (CDKN2B-AS1) was discovered to be the most upregulated among the 14 lncRNAs that were significantly overexpressed in KIRC and related to shorter survival. Functionally, CDKN2B-AS1 depletion suppressed cell proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, CDKN2B-AS1 exerted its oncogenic activity by recruiting the CREB-binding protein and SET and MYND domain-containing 3 epigenetic-modifying complex to the promoter region of Ndc80 kinetochore complex component (NUF2), where it epigenetically activated NUF2 transcription by augmenting local H3K27ac and H3K4me3 modifications. Moreover, we also showed that CDKN2B-AS1 interacted with and was stabilized by insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an oncofetal protein showing increased levels in KIRC. The Kaplan–Meier method and receiver operating curve analysis revealed that patients whose IGF2BP3, CDKN2B-AS1 and NUF2 are all elevated showed the shortest survival time, and the combined panel (containing IGF2BP3, CDKN2B-AS1, and NUF2) possessed the highest accuracy in discriminating high-risk from low-risk KIRC patients. Thus, we conclude that the stabilization of CDKN2B-AS1 by IGF2BP3 drives the malignancy of KIRC through epigenetically activating NUF2 transcription and that the IGF2BP3/CDKN2B-AS1/NUF2 axis may be an ideal prognostic and diagnostic biomarker and therapeutic target for KIRC.

Knockdown of long non-coding RNA CDKN2B-AS1 suppresses the progression of breast cancer by miR-122-5p/STK39 axis

“…It is consistent with the previous other studies about its role in most cancers, which indicated that CDKN2B-AS1 exerted a pro-cancer effect [ 40–42 ]. For examples, in renal clear cell carcinoma, lncRNA CDKN2B-AS1 affected the malignancy through epigenetically activating NUF2 (NUF2 Component of NDC80 Kinetochore Complex) transcription [ 16 ]. Besides, CDKN2B-AS1 had a stimulative function in osteosarcoma and facilitates lung cancer development through their respective ways of regulation [ 43 ].…”

“…The lncRNA CDKN2B Antisense RNA 1 (CDKN2B-AS1) is located within the CDKN2B-CDKN2A (Cyclin Dependent Kinase Inhibitor 2B, Cyclin Dependent Kinase Inhibitor 2A) gene cluster at chromosome 9p21 [16]. It was reported that lncRNA CDKN2B-AS1 is associated with a number of pathologies, such as cardiovascular disease, Alzheimer's disease and type-2 diabetes [17][18][19].…”

CDKN2B-AS1 Promotes Malignancy as a Novel Prognosis-Related Molecular Marker in the Endometrial Cancer Immune Microenvironment

“…CDKN2B-AS1 is a multifunctional lncRNA that exerts carcinogenic effects in various tumors. In renal clear cell carcinoma, CDKN2B-AS1 exerts its carcinogenic activity by recruiting CREB-binding protein and three epigenetic modification complexes containing SET and MYND domains to the promoter region of the Ndc80 mitochondrial complex (NUF2) ( Xie et al, 2021 ). In lung cancer, CDKN2B-AS1 acts as a cavernous body by adsorbing miR-378b and regulating miR-378b/NR2C2 to promote cancer development ( Wang et al, 2020 ).…”

Structures and target RNA preferences of the RNA-binding protein family of IGF2BPs: An overview

“…A plethora of studies on IMPs describes their functional contexts, including mRNA transport (Eom et al, 2003;Farina et al, 2003;Kwon et al, 2002;Nielsen et al, 2001;Song et al, 2015), mRNA protection (Doyle et al, 1998;Jonson et al, 2014;Muller et al, 2018;Weidensdorfer et al, 2009), progression of various cancers (Doyle et al, 1998;Ioannidis et al, 2003Ioannidis et al, , 2005Liao et al, 2004;Wu et al, 2019), alternative splicing (Xueqing et al, 2020), diabetes and fatty acid metabolism (Regue et al, 2019), and m 6 A-methylation (Huang et al, 2018b). Other overview articles summarize these functions in an integrative (Bell et al, 2013;Degrauwe et al, 2016;Tong et al, 2018) or paralog-focused manner (Christiansen et al, 2009;Dai, 2020;Findeis-Hosey and Xu, 2012;Huang et al, 2018b;Lederer et al, 2014;Mancarella and Scotlandi, 2019;Wang et al, 2021;Xie et al, 2021).…”