2. Academic Validation
  3. HNRNPC lactylation promotes pancreatic cancer progression through mediating the alternative splicing of PAK6

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

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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