2. Academic Validation
  3. YTHDC1 lactylation regulates its phase separation to enhance target mRNA stability and promote RCC progression

YTHDC1 lactylation regulates its phase separation to enhance target mRNA stability and promote RCC progression

  • Mol Cell. 2025 Jul 17;85(14):2733-2748.e7. doi: 10.1016/j.molcel.2025.06.017.
Chenyun Dai 1,  Yuangui Tang 2,  Huihui Yang 2,  Junfang Zheng 3
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China; State Key Laboratory of Neurology and Oncology Drug Development, Nanjing 210018, China.
  • 2 Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
  • 3 Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China. Electronic address: zhengjf@ccmu.edu.cn.
PMID: 40680722 DOI: 10.1016/j.molcel.2025.06.017
Abstract

The hypoxic and lactate-enriched microenvironment of renal cell carcinoma (RCC) provides favorable conditions for aberrant lysine lactylation (Kla). However, the functional role and mechanistic basis of Kla in RCC progression remain elusive. Here, we showed an elevated global Kla level in human RCC tissues and cells, which promoted RCC malignancy. Through lactylome analysis of human RCC cells under hypoxia-mimicking conditions, we found that the m6A reader YT521-B homology (YTH) domain-containing 1 (YTHDC1) is modified by Kla at K82. YTHDC1K82la, mediated by p300 under hypoxia, promotes RCC malignancy both in vitro and in vivo. Mechanistically, YTHDC1K82la increases YTHDC1 phase separation, leading to the expansion of nuclear condensates and safeguarding oncogenic transcripts BCL2 and E2F2 from degradation by the poly A-tail exosome targeting (PAXT)-exosome complex in human RCC cells. Our results demonstrated that augmented Kla advances RCC progression by modulating phase separation and thereby regulating the stability of YTHDC1 target genes.

Keywords

BCL2; E2F2; YTHDC1; lactylation; phase-separated condensate; renal cancer.

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