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Enhanced osteopontin splicing regulated by RUNX2 is HDAC-dependent and induces invasive phenotypes in NSCLC cells

Huang, Jing, Chang, Siyuan, Lu, Yabin, Wang, Jing, Si, Yang, Zhang, Lijian, Cheng, Shan and Jiang, Wen G. ORCID: https://orcid.org/0000-0002-3283-1111 2019. Enhanced osteopontin splicing regulated by RUNX2 is HDAC-dependent and induces invasive phenotypes in NSCLC cells. Cancer Cell International 19 (1) , 306. 10.1186/s12935-019-1033-5

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Abstract

Background Increased cell mobility is a signature when tumor cells undergo epithelial-to-mesenchymal transition. TGF-β is a key stimulating factor to promote the transcription of a variety of downstream genes to accelerate cancer progression and metastasis, including osteopontin (OPN) which exists in several functional forms as different splicing variants. In non-small cell lung cancer cells, although increased total OPN expression was observed under various EMT conditions, the exact constitution and the underlining mechanism towards the generation of such OPN splicing isoforms was poorly understood. Methods We investigated the possible mechanisms of osteopontin splicing variant and its role in EMT and cancer metastasis using NSCLC cell line and cell and molecular biology techniques. Results In this study, we determined that OPNc, an exon 4 excluded shorter form of Opn gene products, appeared to be more potent to promote cell invasion. The expression of OPNc was selectively increased to higher abundance during EMT following TGF-β induction. The switching from OPNa to OPNc could be enhanced by RUNX2 (a transcription factor that recognizes the Opn gene promoter) overexpression, but appeared to be strictly in a HDAC dependent manner in A549 cells. The results suggested the increase of minor splicing variant of OPNc required both (1) the enhanced transcription from its coding gene driven by specific transcription factors; and (2) the simultaneous modulation or fluctuation of the coupled splicing process that depends to selective classed of epigenetic regulators, predominately HDAC family members.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: BioMed Central
ISSN: 1475-2867
Funders: High Caliber Teachers in Beijing Municipal Universities during the �13th Five-year Plan� (IDHT20170516).
Date of First Compliant Deposit: 25 November 2019
Date of Acceptance: 12 November 2019
Last Modified: 05 May 2023 15:44
URI: https://orca.cardiff.ac.uk/id/eprint/127097

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