Long noncoding RNA SNHG12 promotes tumour progression and sunitinib resistance by upregulating CDCA3 in renal cell carcinoma

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Abstract

Renal cell carcinoma (RCC) is one of the most frequently observed malignant tumours in the urinary system and targeted drug resistance is quite common in RCC. Long noncoding RNA SNHG12 (lncRNA SNHG12) has emerged as a key molecule in numerous human cancers, but its functions in renal cell carcinoma (RCC) sunitinib resistance remain unclear. In this study, we found SNHG12 was highly expressed in RCC tissues and in sunitinib-resistant RCC cells and was associated with a poor clinical prognosis. SNHG12 promoted RCC proliferation, migration, invasion and sunitinib resistance via CDCA3 in vitro. Mechanically, SNHG12 bound to SP1 and prevented the ubiquitylation-dependent proteolysis of SP1. Stabilised SP1 bound to a specific region in the promoter of CDCA3 and increased CDCA3 expression. Furthermore, in vivo experiments showed that SNHG12 increased tumour growth and that knocking down SNHG12 could reverse RCC sunitinib resistance. Our study revealed that the lncRNA SNHG12/SP1/CDCA3 axis promoted RCC progression and sunitinib resistance, which could provide a new therapeutic target for sunitinib-resistant RCC.

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Long noncoding RNA as modular scaffold of histone modification complexes.

Miao-Chih Tsai, Ohad Manor, Yue Wan … (2010)

Long intergenic noncoding RNAs (lincRNAs) regulate chromatin states and epigenetic inheritance. Here, we show that the lincRNA HOTAIR serves as a scaffold for at least two distinct histone modification complexes. A 5' domain of HOTAIR binds polycomb repressive complex 2 (PRC2), whereas a 3' domain of HOTAIR binds the LSD1/CoREST/REST complex. The ability to tether two distinct complexes enables RNA-mediated assembly of PRC2 and LSD1 and coordinates targeting of PRC2 and LSD1 to chromatin for coupled histone H3 lysine 27 methylation and lysine 4 demethylation. Our results suggest that lincRNAs may serve as scaffolds by providing binding surfaces to assemble select histone modification enzymes, thereby specifying the pattern of histone modifications on target genes.

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LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs

Liuqing Yang, Chunru Lin, Chunyu Jin … (2013)

While recent studies indicated roles of long non-coding RNAs (lncRNAs) in physiologic aspects of cell-type determination and tissue homeostasis 1 yet their potential involvement in regulated gene transcription programs remain rather poorly understood. Androgen receptor (AR) regulates a large repertoire of genes central to the identity and behavior of prostate cancer cells 2 , and functions in a ligand-independent fashion in many prostate cancers when they become hormone refractory after initial androgen deprivation therapy 3 . Here, we report that two lncRNAs highly overexpressed in aggressive prostate cancer, PRNCR1 and PCGEM1, bind successively to the AR and strongly enhance both ligand-dependent and ligand-independent AR-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the C-terminally acetylated AR on enhancers and its association with DOT1L appear to be required for recruitment of the second lncRNA, PCGEM1, to the DOT1L-mediated methylated AR N-terminus. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited Pygopus2 PHD domain proves to enhance selective looping of AR-bound enhancers to target gene promoters in these cells. In “resistant” prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full length AR, causing ligand-independent activation of the AR transcriptional program and cell proliferation. Conditionally-expressed short hairpin RNA (shRNA) targeting of these lncRNAs in castration-resistant prostate cancer (CRPC) cell lines strongly suppressed tumor xenograft growth in vivo. Together, these results suggest that these overexpressed lncRNAs can potentially serve as a required component of castration-resistance in prostatic tumors.

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Is Open Access

Mechanisms and Functions of Long Non-Coding RNAs at Multiple Regulatory Levels

Xiaopei Zhang, Wei. Wang, Weidong Zhu … (2019)

Long non-coding (lnc) RNAs are non-coding RNAs longer than 200 nt. lncRNAs primarily interact with mRNA, DNA, protein, and miRNA and consequently regulate gene expression at the epigenetic, transcriptional, post-transcriptional, translational, and post-translational levels in a variety of ways. They play important roles in biological processes such as chromatin remodeling, transcriptional activation, transcriptional interference, RNA processing, and mRNA translation. lncRNAs have important functions in plant growth and development; biotic and abiotic stress responses; and in regulation of cell differentiation, the cell cycle, and the occurrence of many diseases in humans and animals. In this review, we summarize the functions and mechanisms of lncRNAs in plants, humans, and animals at different regulatory levels.

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Author and article information

Contributors

Ke Chen: shenke@hust.edu.cn

Xiaoping Zhang: xzhang@hust.edu.cn

Journal

Journal ID (nlm-ta): Cell Death Dis

Journal ID (iso-abbrev): Cell Death Dis

Title: Cell Death & Disease

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-4889

Publication date (Electronic): 8 July 2020

Publication date PMC-release: 8 July 2020

Publication date Collection: July 2020

Volume: 11

Issue: 7

Electronic Location Identifier: 515

Affiliations

[1 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Department of Urology, Union Hospital, Tongji Medical College, , Huazhong University of Science and Technology, ; No. 1277 Jiefang Avenue, 430022 Wuhan, China

[2 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, , Huazhong University of Science and Technology, ; No. 1277 Jiefang Avenue, 430022 Wuhan, China

[3 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Department of Pathogenic Biology, School of Basic Medicine, , Huazhong University of Science and Technology, ; No. 13 Hangkong Road, 430030 Wuhan, China

Author information

Hongmei Yang http://orcid.org/0000-0003-0924-5795

Article

Publisher ID: 2713

DOI: 10.1038/s41419-020-2713-8

PMC ID: 7343829

PubMed ID: 32641718

SO-VID: 41c2afc3-ffac-4d90-956a-5670f5eacc5c

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 3 April 2020

Date revision received : 9 June 2020

Date accepted : 15 June 2020

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 81672528

Award ID: 81874090

Award Recipient : Xiaoping Zhang

Funded by: National Key R&D Program of China,Grant Nos. 2017YFB1303100

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ScienceOpen disciplines: Cell biology

Keywords: renal cell carcinoma,mechanisms of disease,long non-coding rnas

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ScienceOpen disciplines: Cell biology

Keywords: renal cell carcinoma, mechanisms of disease, long non-coding rnas

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Long noncoding RNA SNHG12 promotes tumour progression and sunitinib resistance by upregulating CDCA3 in renal cell carcinoma

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Evolutionary Cell Biology

Most cited references 29

Long noncoding RNA as modular scaffold of histone modification complexes.

LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs

Mechanisms and Functions of Long Non-Coding RNAs at Multiple Regulatory Levels

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