TTC22 promotes m6A-mediated WTAP expression and colon cancer metastasis in an RPL4 binding-dependent pattern
Abin You1,2, Wei Tian3, Hongfan Yuan1
1Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Etiology, Peking University Cancer Hospital and Institute, Beijing, 100142, China.
Abstract:
WTAP, an essential component of the RNA N-6-methyladenosine (m6A) modification complex, guides METLL3-METLL14 heteroduplexes to target RNAs in the nuclear speckles of mammalian cells. Here, we show that TTC22 is widely coexpressed with WTAP and FTO in many human tissues by mining Genotype-Tissue Expression (GTEx) datasets. Our results indicate that the direct interaction of TTC22 with 60S ribosomal protein L4 (RPL4) promotes the binding of WTAP mRNA to RPL4, enhances the stability and translation efficiency of WTAP mRNA, and consequently increases the level of WTAP protein. Also, WTAP mRNA itself is an m6A target and YTHDF1 is characterized as an essential m6A binding protein interacting with m6A-modified WTAP mRNA. TTC22 triggers a positive feedback loop between WTAP expression and WTAP mRNA m6A modification, leading to an increased m6A level in total RNA. The knockdown of RPL4, WTAP, or YTHDF1 expression diminishes the TTC22-induced increase in the m6A level of total RNA. Thus, TTC22 caused dramatic expression changes in genes related to metabolic pathways, ribosomal biogenesis, the RNA spliceosome, and microorganism infections. Importantly, TTC22 upregulates the expression of SNAI1 by increasing m6A level and thus promotes lung metastases of colon cancer cells in mice. In conclusion, our study showed that TTC22 upregulates WTAP and SNAI1 expression, which contributes to TTC22-induced colon cancer metastasis.
Insights
TTC22 protein enhances WTAP expression by stabilizing its mRNA, increasing RNA N-6-methyladenosine (m6A) modification. This process promotes colon cancer metastasis by upregulating SNAI1.
Area of Science:
- Molecular Biology
- Cancer Research
- Epigenetics
Background:
- WTAP is a key component of the RNA N-6-methyladenosine (m6A) modification complex.
- m6A modification regulates gene expression and is implicated in various biological processes, including cancer.
Purpose of the Study:
- To investigate the role of TTC22 in regulating WTAP expression and m6A modification.
- To elucidate the mechanism by which TTC22 influences WTAP mRNA stability and translation.
- To determine the impact of TTC22 on colon cancer metastasis.
Main Methods:
- Bioinformatic analysis of Genotype-Tissue Expression (GTEx) datasets to assess coexpression of TTC22, WTAP, and FTO.
- Co-immunoprecipitation assays to confirm the interaction between TTC22 and RPL4.
- Western blotting and qRT-PCR to measure protein and mRNA levels of WTAP.
- RNA immunoprecipitation followed by sequencing (RIP-seq) to identify m6A targets.
- In vivo mouse models to study colon cancer lung metastasis.
Main Results:
- TTC22 is coexpressed with WTAP and FTO in human tissues.
- TTC22 directly interacts with RPL4, promoting WTAP mRNA binding to RPL4, enhancing its stability and translation, thus increasing WTAP protein levels.
- WTAP mRNA is an m6A target, and YTHDF1 binds to m6A-modified WTAP mRNA.
- TTC22 establishes a positive feedback loop involving WTAP expression and WTAP mRNA m6A modification, leading to increased global m6A levels.
- TTC22 induces significant changes in genes related to metabolic pathways, ribosomal biogenesis, RNA spliceosome, and infections.
- TTC22 upregulates SNAI1 expression via increased m6A levels, promoting colon cancer lung metastasis in mice.
Conclusions:
- TTC22 plays a crucial role in upregulating WTAP expression and m6A modification.
- TTC22-mediated upregulation of WTAP and SNAI1 contributes to colon cancer metastasis.
- TTC22 represents a potential therapeutic target for colon cancer treatment.
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