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EBioMedicine. 2019 Aug 10. pii: S2352-3964(19)30510-9. doi: 10.1016/j.ebiom.2019.07.068. [Epub ahead of print]

N6-methyladenosine modification of ITGA6 mRNA promotes the development and progression of bladder cancer.

Author information

1
Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, 510080 Guangzhou, China; Department of Physiology, Zunyi Medical College, Guizhou 563000, China.
2
Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, 510080 Guangzhou, China.
3
Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangdong Key Laboratory of Urology, Guangzhou 510230, China.
4
Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, China.
5
Department of Pathology and the Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06519, USA.
6
Department of Breast Surgery, Guangdong Provincial People's Hospital, Guangzhou 510080, China. Electronic address: bayberry513@yahoo.com.
7
Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, 510080 Guangzhou, China. Electronic address: jiweidong@mail.sysu.edu.cn.

Abstract

BACKGROUND:

Accumulating evidence has revealed the critical roles of N6-methyladenosine (m6A) modification of mRNA in various cancers. However, the biological function and regulation of m6A in bladder cancer (BC) are not yet fully understood.

METHODS:

We performed cell phenotype analysis and established in vivo mouse xenograft models to assess the effects of m6A-modified ITGA6 on BC growth and progression. Methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation and luciferase reporter and mutagenesis assays were used to define the mechanism of m6A-modified ITGA6. Immunohistochemical analysis was performed to assess the correlation between METTL3 and ITGA6 expression in bladder cancer patients.

FINDINGS:

We show that the m6A writer METTL3 and eraser ALKBH5 altered cell adhesion by regulating ITGA6 expression in bladder cancer cells. Moreover, upregulation of ITGA6 is correlated with the increase in METTL3 expression in human BC tissues, and higher expression of ITGA6 in patients indicates a lower survival rate. Mechanistically, m6A is highly enriched within the ITGA6 transcripts, and increased m6A methylations of the ITGA6 mRNA 3'UTR promotes the translation of ITGA6 mRNA via binding of the m6A readers YTHDF1 and YTHDF3. Inhibition of ITGA6 results in decreased growth and progression of bladder cancer cells in vitro and in vivo. Furthermore, overexpression of ITGA6 in METTL3-depleted cells partially restores the BC adhesion, migration and invasion phenotypes.

INTERPRETATION:

Our results demonstrate an oncogenic role of m6A-modified ITGA6 and show its regulatory mechanisms in BC development and progression, thus identifying a potential therapeutic target for BC. FUND: This work was supported by National Natural Science Foundation of China (81772699, 81472999).

KEYWORDS:

Bladder cancer; ITGA6; METTL3; N(6)-methyladenosine; Progression

PMID:
31409574
DOI:
10.1016/j.ebiom.2019.07.068
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