HNRNPC lactylation promotes pancreatic cancer progression through mediating the alternative splicing of PAK6

  • Cancer Lett. 2025 Dec 22:639:218230. doi: 10.1016/j.canlet.2025.218230.
BoHao Li  1 ,  HanXiang Zhan  2 ,  Fei Gao  1 ,  MingXin Wen  3 ,  Yunhan Ma  4 ,  YuChen Xiu  1 ,  ZhenYa Liu  2 ,  KaiWei Huang  1 ,  YunShan Wang  5 ,  GuangWei Wei  6 ,  YangMiao Duan  7
Affiliations
  • 1. Department of Cell Biology and Key Laboratory of Experimental Teratology, Ministry of Education, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
  • 2. Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China.
  • 3. Department of Anatomy, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
  • 4. Department of Thyroid and Breast Surgery, The 960th Hospital of the Chinese People's Liberation Army (PLA) Joint Logistics Support Force, Jinan, Shandong, 250012, China.
  • 5. Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
  • 6. Department of Cell Biology and Key Laboratory of Experimental Teratology, Ministry of Education, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. Electronic address: [email protected].
  • 7. Department of Cell Biology and Key Laboratory of Experimental Teratology, Ministry of Education, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. Electronic address: [email protected].
PMID: 41435694 DOI: 10.1016/j.canlet.2025.218230
Abstract

Pancreatic Cancer (PC) is a highly malignant and lethal tumor in gastrointestinal tract. Lactate accumulation is a classical feature of metabolic reprogramming in cancers. Lactate-derived lysine lactylation (Kla) is identified as a new type of post-translational modifications (PTMs), which is confirmed to be involved in multiple biological processes. However, the cancer-specific regulation of protein Kla in PC requires further elucidation. Here, we report a range of dysregulated Kla sites specifically related to RNA splicing in human pancreatic Cancer, leading to the observation that the Kla at lysine 176 of heterogeneous nuclear ribonucleoprotein C (HNRNPC K176la) is significantly elevated in PC. Blocking HNRNPC K176la dramatically inhibits pancreatic Cancer growth and metastasis. Mechanistically, K176la strengthened the binding of HNRNPC with poly-U motifs in p21-activated kinase 6 (PAK6) pre-mRNA, facilitating the expression of the oncogenic isoform PAK6S. Therefore, our study identifies a number of cancer-specific Kla sites spanned on alternative splicing (AS)-related proteins and unravels the significance of HNRNPC K176la in RNA splicing and PC development.

Keywords
Alternative splicing; HNRNPC; Lactylation; PAK6; Pancreatic cancer.
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