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Alternative Splicing of EZH2 pre-mRNA by SF3B3 Contributes to the Tumorigenic Potential of Renal Cancer.

Publication ,  Journal Article
Chen, K; Xiao, H; Zeng, J; Yu, G; Zhou, H; Huang, C; Yao, W; Xiao, W; Hu, J; Guan, W; Wu, L; Huang, J; Huang, Q; Xu, H; Ye, Z
Published in: Clin Cancer Res
July 1, 2017

Purpose: Deregulation or mutation of the EZH2 gene causes various tumors, including clear cell renal cell carcinoma (ccRCC). Although several splice variants of EZH2 have been identified, little is known about how EZH2 splicing is regulated or the contribution of alternative splicing to its protumorigenic functions.Experimental Design: We conducted RT-PCR, Western blot analysis, and IHC techniques to examine EZH2 and its alternative splicing transcript expression in renal cancer tissue and renal cancer cell lines. Proliferation, migration, clonogenicity, and tumorigenicity of renal cancer cells either exhibiting knockdown of EZH2 or its splicing factor SF3B3 were assessed by CCK8, Transwell assay, and murine xenograft experiments.Results: We found that the inclusion of alternative EZH2 exon 14 was significantly increased in ccRCC samples and renal cancer cell lines. In ccRCC lines, enforced expression of EZH2Δ14 inhibited, and EZH2 promoted, cell growth, migration, proliferation, and tumorigenicity in a xenograft model. Mechanistic studies demonstrated that EZH2Δ14 isoform functions as a dominant-negative inhibitor of full-length EZH2. Coexpression of EZH2Δ14 variant with full-length EZH2 not only abrogated DAB2IP and HOXA9 suppression but also inhibited EZH2-driven tumorigenesis. Strikingly, the splicing factor SF3B3 stimulates inclusion of exon14 and has pro-proliferative activity. Importantly, the upregulation of SF3B3 expression observed in clinical ccRCC samples parallels the increased inclusion of EZH2 exon14, and the SF3B3 level is associated with higher tumor stage and poor overall survival.Conclusions: These results suggest SF3B3 as a key regulator of EZH2 pre-mRNA splicing and SF3B3 may represent a novel prognostic factor and potential therapeutic target in ccRCC. Clin Cancer Res; 23(13); 3428-41. ©2016 AACR.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

July 1, 2017

Volume

23

Issue

13

Start / End Page

3428 / 3441

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • RNA Splicing Factors
  • RNA Precursors
  • Protein Isoforms
  • Oncology & Carcinogenesis
  • Mice
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Enhancer of Zeste Homolog 2 Protein
  • Cell Proliferation
 

Citation

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MLA
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Chen, K., Xiao, H., Zeng, J., Yu, G., Zhou, H., Huang, C., … Ye, Z. (2017). Alternative Splicing of EZH2 pre-mRNA by SF3B3 Contributes to the Tumorigenic Potential of Renal Cancer. Clin Cancer Res, 23(13), 3428–3441. https://doi.org/10.1158/1078-0432.CCR-16-2020
Chen, Ke, Haibing Xiao, Jin Zeng, Gan Yu, Hui Zhou, Chunhua Huang, Weimin Yao, et al. “Alternative Splicing of EZH2 pre-mRNA by SF3B3 Contributes to the Tumorigenic Potential of Renal Cancer.Clin Cancer Res 23, no. 13 (July 1, 2017): 3428–41. https://doi.org/10.1158/1078-0432.CCR-16-2020.
Chen K, Xiao H, Zeng J, Yu G, Zhou H, Huang C, et al. Alternative Splicing of EZH2 pre-mRNA by SF3B3 Contributes to the Tumorigenic Potential of Renal Cancer. Clin Cancer Res. 2017 Jul 1;23(13):3428–41.
Chen, Ke, et al. “Alternative Splicing of EZH2 pre-mRNA by SF3B3 Contributes to the Tumorigenic Potential of Renal Cancer.Clin Cancer Res, vol. 23, no. 13, July 2017, pp. 3428–41. Pubmed, doi:10.1158/1078-0432.CCR-16-2020.
Chen K, Xiao H, Zeng J, Yu G, Zhou H, Huang C, Yao W, Xiao W, Hu J, Guan W, Wu L, Huang J, Huang Q, Xu H, Ye Z. Alternative Splicing of EZH2 pre-mRNA by SF3B3 Contributes to the Tumorigenic Potential of Renal Cancer. Clin Cancer Res. 2017 Jul 1;23(13):3428–3441.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

July 1, 2017

Volume

23

Issue

13

Start / End Page

3428 / 3441

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • RNA Splicing Factors
  • RNA Precursors
  • Protein Isoforms
  • Oncology & Carcinogenesis
  • Mice
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Enhancer of Zeste Homolog 2 Protein
  • Cell Proliferation