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NUF2 Drives Clear Cell Renal Cell Carcinoma by Activating HMGA2 Transcription through KDM2A-mediated H3K36me2 Demethylation.

ABSTRACT: The poor sensitivity of clear cell renal cell carcinoma (ccRCC) to conventional chemotherapy and radiotherapy makes its treatment challenging. The Ndc80 kinetochore complex component (NUF2) is involved in the development and progression of several cancers. However, its role in ccRCC remains unclear. In this study, we investigated the biological functions and underlying mechanism of NUF2 in ccRCC. We found that NUF2 expression was increased in ccRCC and associated with poor prognosis. Altering NUF2 level affected cell proliferation, migration, and invasion. Moreover, NUF2 acted as a potential oncogene to promote the progression of ccRCC through epigenetic activation of high-mobility group AT-hook 2 (HMGA2) transcription by suppressing lysine demethylase 2A expression and affecting its occupancy on the HMGA2 promoter region to regulate histone H3 lysine 36 di-methylation modification. In addition, Kaplan-Meier and multivariate analysis revealed that patients whose NUF2 and HMGA2 were both elevated showed the shortest survival; and the number of upregulated markers acted as an independent predictor to evaluate survival probability. Thus, our results demonstrate that NUF2 promotes ccRCC progression, at least partly by epigenetically regulating HMGA2 transcription, and that the NUF2-HMGA2 axis could be an ideal therapeutic target and a promising prognostic indicator for ccRCC.

SUBMITTER: Lin J

PROVIDER: S-EPMC9254462 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

Dataset Information

NUF2 Drives Clear Cell Renal Cell Carcinoma by Activating HMGA2 Transcription through KDM2A-mediated H3K36me2 Demethylation.

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