2. Academic Validation
  3. Lactylation increases the stability of RBM15 to drives m6A modification in non-small-cell lung cancer cells

Lactylation increases the stability of RBM15 to drives m6A modification in non-small-cell lung cancer cells

  • FASEB J. 2025 Mar 31;39(6):e70493. doi: 10.1096/fj.202500020RR.
Zhenyu Zhao 1 2,  Zhe Zhang 1 2,  Qidong Cai 1 2,  Rui Yang 1 2,  Hengxing Liang 1 2 3,  Banglun Qian 1 2,  Bing Xiao 4 5,  Yupeng Jiang 6,  Li Wang 1 2,  Xiang Wang 1 2,  Juan Cai 7
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, China.
  • 2 Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, China.
  • 3 Department of Thoracic Surgery, Guilin Hospital of the Second Xiangya Hospital of Central South University, Guilin, China.
  • 4 Department of Emergency Medicine, Second Xiangya Hospital of Central South University, Changsha, China.
  • 5 Department of Emergency Medicine, Guilin Hospital of the Second Xiangya Hospital of Central South University, Guilin, China.
  • 6 Department of Oncology, Second Xiangya Hospital of Central South University, Changsha, China.
  • 7 National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, China.
PMID: 40135634 DOI: 10.1096/fj.202500020RR
Abstract

Emerging evidence supports the involvement of N6-Methyladenosine (m6A) modification in the etiology and progression of lung adenocarcinoma (LUAD), highlighting its potential as a therapeutic target. RNA-binding protein 15 (RBM15) is a well-known m6A writer protein that enhances global m6A methylation levels by associating with the METTL3-WTAP complex. Previous studies have demonstrated that RBM15 is upregulated and exerts an oncogenic role in LUAD by promoting the N6-methyladenosine-mediated mRNA stability. However, the regulatory mechanisms of RBM15 remain elusive. In this study, we observed that L-lactate upregulates RBM15 protein levels in non-small-cell lung Cancer cell lines A549 and H23 in a time- and dosage-dependent manner. Furthermore, we discovered that lactate uptake mediated by Monocarboxylate Transporter 1 (MCT1) is essential for RBM15 induction. Subsequent investigations revealed that L-lactate promotes lactylation of RBM15 majorly at Lys850 (K850), while histone deacetylase 3 (HDAC3) acts as the delactylase for RBM15. Importantly, lactylation of RBM15 stabilizes itself by inhibiting proteasome-mediated ubiquitin degradation. Mutation of the lactylation site K850R disrupts the association between RBM15 and METTL3, leading to a reduction in global m6A levels. Moreover, K850R significantly abrogated RBM15-mediated cell proliferation and migration in LUAD cells. Collectively, these findings unveil lactylation as a novel regulatory mechanism affecting both stability and m6A methylation activity of RBM15 in LUAD cells.

Keywords

RBM15; lactylation; m6A modification; ubiquitination degradation.

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