TTC22 promotes m6A-mediated WTAP expression and colon cancer metastasis in an RPL4 binding-dependent pattern

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.