2. Academic Validation
  3. Lactylation-stabilized NOL6 promotes colorectal cancer progression via STAMBP-mediated YY1 deubiquitination and c-Myc transcription upregulation

Lactylation-stabilized NOL6 promotes colorectal cancer progression via STAMBP-mediated YY1 deubiquitination and c-Myc transcription upregulation

  • Cell Rep. 2025 Dec 26;45(1):116774. doi: 10.1016/j.celrep.2025.116774.
Hao Zhang 1,  Ye Han 2,  Jiaqi Wang 1,  Chunlin Wang 1,  Zewen Chang 1,  Jun Xiang 1,  Hanqing Hu 1,  Ziming Yuan 1,  Nana Zhang 1,  Yuliuming Wang 1,  Chenkai Zhang 1,  Yunxiao Liu 1,  Chengwei Wu 2,  Jian Ma 3,  Xianli Zhou 4,  Guiyu Wang 5
Affiliations

Affiliations

  • 1 Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150000, China.
  • 2 In-Patient Ultrasound Department, The Second Affiliated Hospital of Harbin Medical University, Harbin 150000, China.
  • 3 School of Basic Medical Sciences, Harbin Medical University, Harbin 150000, China.
  • 4 In-Patient Ultrasound Department, The Second Affiliated Hospital of Harbin Medical University, Harbin 150000, China. Electronic address: [email protected].
  • 5 Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150000, China. Electronic address: [email protected].
PMID: 41456274 DOI: 10.1016/j.celrep.2025.116774
Abstract

Colorectal Cancer (CRC) represents a significant menace to human health, but its molecular pathogenesis remains unclear. Herein, we explored the functional role of spindle and nucleolar protein 6 (NOL6) in CRC progression. In this study, we found that NOL6 was significantly overexpressed in CRC tissues and correlated with advanced tumor stages and poor patient prognosis. Mechanistically, NOL6 recruited the deubiquitinating enzyme STAMBP to remove K48-linked polyubiquitin chains from Yin Yang 1 (YY1) at lysine 339, preventing YY1 degradation and enhancing c-Myc transcription. A feedback loop was identified where c-Myc directly bound to the NOL6 promoter, reinforcing NOL6 expression. Additionally, lactylation at lysine 54 (K54) of NOL6 stabilized NOL6 by inhibiting its ubiquitination and proteasomal degradation. Targeting NOL6-K54 lactylation with a cell-penetrating peptide inhibitor (K54-pe4) suppressed CRC cell proliferation and metastases in vivo without apparent toxicity. These findings establish a novel regulatory axis (NOL6-STAMBP-YY1-Myc) strengthened by lactylation, highlighting NOL6 as a potential therapeutic target for CRC.

Keywords

CP: Cancer; NOL6; colorectal cancer; lactylation; ubiquitination.

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