# CDK13 drives clear cell renal carcinoma through METTL16-mediated m6A modification of ACLY mRNA

## TL;DR

CDK13 promotes fat production in kidney cancer by modifying RNA through METTL16, offering a new target for treatment.

## Contribution

CDK13 is identified as a driver of lipid metabolism in ccRCC via m6A modification of ACLY mRNA through METTL16 phosphorylation.

## Key findings

- CDK13 overexpression correlates with advanced tumor stage and poor prognosis in ccRCC.
- CDK13 phosphorylates METTL16, enhancing m6A modification of ACLY mRNA to increase acetyl-CoA production.
- Disrupting the CDK13–METTL16–ACLY axis reduces lipid accumulation and tumor growth in preclinical models.

## Abstract

Cyclin-dependent kinase 13 (CDK13) has emerged as a critical regulator of oncogenic metabolism, but its role in rewiring lipid metabolism in clear cell renal cell carcinoma (ccRCC) remains undefined. Here we identify CDK13 as a master orchestrator of lipid dysregulation in ccRCC, demonstrating that it drives de novo lipogenesis through a phosphorylation-dependent RNA N6-methyladenosine (m6A) modification axis. Clinically, CDK13 overexpression correlates with advanced tumor stage, poor prognosis and aberrant lipid accumulation in patient-derived ccRCC tissues. Mechanistically, CDK13 directly phosphorylates the methyltransferase-like protein 16 (METTL16) at Ser329, augmenting its catalytic activity to install m6A modifications on ATP-citrate synthase (ACLY) messenger RNA. These m6A marks are selectively recognized by the YTHDC2 reader protein, leading to mRNA stabilization and increased acetyl-CoA production, which fuels lipogenesis and sustains ccRCC aggressiveness. Genetic or pharmacological disruption of the CDK13–METTL16–ACLY axis synergistically suppresses lipid deposition, tumor growth and metastasis in vitro and in vivo. Notably, targeting CDK13 with the small-molecule inhibitor 1NM-PP1 potentiates METTL16 depletion-mediated anticancer effects. Our findings establish a kinase-RNA modifier axis that links CDK13 to epitranscriptomic control of lipid metabolism, positioning the CDK13–METTL16–ACLY pathway as a promising target for precision therapies against ccRCC.

Clear cell renal cell carcinoma (ccRCC) is a common type of kidney cancer known for abnormal fat buildup in cells. This study explores how a protein called cyclin-dependent kinase 13 (CDK13) might influence this process. Researchers found that CDK13 is often present in high amounts in ccRCC and is linked to worse outcomes for patients. The study involves analyzing cancer cells and tissues from patients, as well as using mouse models to understand the role of CDK13. They discovered that CDK13 helps increase the production of fats in cancer cells by affecting another protein, METTL16, which modifies RNA. This modification helps stabilize the RNA of a key enzyme, ACLY, which is crucial for fat production. Findings suggest that targeting the CDK13–METTL16–ACLY pathway could be a new way to treat ccRCC by disrupting the cancer’s ability to produce fats.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.