NAT10-mediated ac⁴C-modified ANKZF1 promotes tumor progression and lymphangiogenesis in clear-cell renal cell...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Lymphatic metastasis is a common and poor prognostic indicator in clear-cell renal cell carcinoma (ccRCC).
• N-acetyltransferase 10 (NAT10) catalyzes mRNA N4-acetylcytidine (ac⁴C) modification, but its role in ccRCC lymphangiogenesis is unknown.

Purpose of the Study:

• To investigate the role of NAT10 in ccRCC lymphangiogenesis.
• To identify NAT10 as a potential therapeutic target for ccRCC intervention.

Main Methods:

• Assessed ac⁴C modification and NAT10 expression in ccRCC using public databases and clinical samples.
• Utilized cellular and mouse models to study NAT10 function.
• Employed RNA sequencing, mass spectrometry, co-immunoprecipitation, RNA immunoprecipitation, immunofluorescence, and site-specific mutation analyses for mechanistic insights.

Main Results:

• NAT10 expression and ac⁴C modification are elevated in ccRCC.
• NAT10 promotes ccRCC progression and lymphangiogenesis by enhancing Yes1-associated transcriptional regulator (YAP1) nuclear import.
• Identified ankyrin repeat and zinc finger peptidyl tRNA hydrolase 1 (ANKZF1) as a NAT10 target, upregulated via NAT10-mediated ac⁴C modification.

Conclusions:

• NAT10 plays a pro-cancer role in ccRCC through acetylation.
• The NAT10/ANKZF1/YAP1 axis is a newly identified pathway driving ccRCC progression and lymphangiogenesis.
• This pathway represents a potential therapeutic target for ccRCC.