Lactylproteome analysis indicates histone H4K12 lactylation as a novel biomarker in triple-negative breast cancer

Zhaolei Cui; Yanhong Li; Yingying Lin; Chaoqiang Zheng; Lingqing Luo; Dan Hu; Yan Chen; Zhenzhou Xiao; Yang Sun

doi:10.3389/fendo.2024.1328679

Lactylproteome analysis indicates histone H4K12 lactylation as a novel biomarker in triple-negative breast cancer

Front Endocrinol (Lausanne). 2024 May 8:15:1328679. doi: 10.3389/fendo.2024.1328679. eCollection 2024.

Authors

Zhaolei Cui¹, Yanhong Li², Yingying Lin¹, Chaoqiang Zheng¹, Lingqing Luo¹, Dan Hu³, Yan Chen¹, Zhenzhou Xiao¹, Yang Sun²

Affiliations

¹ Laboratory of Biochemistry and Molecular Biology Research, Department of Laboratory Medicine, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China.
² Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China.
³ Department of Pathology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China.

Abstract

Objective: The established link between posttranslational modifications of histone and non-histone lysine (K) residues in cell metabolism, and their role in cancer progression, is well-documented. However, the lactylation expression signature in triple-negative breast cancer (TNBC) remains underexplored.

Methods: We conducted a comprehensive lactylproteome profiling of eight pairs of TNBC samples and their matched adjacent tissues. This was achieved through 4-Dimensional label-free quantitative proteomics combined with lactylation analysis (4D-LFQP-LA). The expression of identified lactylated proteins in TNBC was detected using immunoblotting and immunohistochemistry (IHC) with specific primary antibodies, and their clinicopathological and prognostic significance was evaluated.

Results: Our analysis identified 58 lactylation sites on 48 proteins, delineating the protein lactylation alteration signature in TNBC. Bioinformatic and functional analyses indicated that these lactylated proteins play crucial roles in regulating key biological processes in TNBC. Notably, lactylation of lysine at position 12 (H4K12lac) in the histone H4 domain was found to be upregulated in TNBC. Further investigations showed a high prevalence of H4K12lac upregulation in TNBC, with positive rates of 93.19% (137/147) and 92.93% (92/99) in TNBC tissue chip and validation cohorts, respectively. H4K12lac expression correlated positively with Ki-67 and inversely with overall survival (OS) in TNBC (HR [hazard ratio] =2.813, 95%CI [credibility interval]: 1.242-6.371, P=0.0164), suggesting its potential as an independent prognostic marker (HR=3.477, 95%CI: 1.324-9.130, P=0.011).

Conclusions: Lactylation is a significant post-translational modification in TNBC proteins. H4K12lac emerges as a promising biomarker for TNBC, offering insights into the lactylation profiles of TNBC proteins and linking histone modifications to clinical implications in TNBC.

Keywords: biomarker; histone H4; lactylation; prognosis; triple negative breast cancer.

MeSH terms

Adult
Biomarkers, Tumor* / metabolism
Female
Histones* / metabolism
Humans
Lysine / metabolism
Middle Aged
Prognosis
Protein Processing, Post-Translational*
Proteome / metabolism
Proteomics / methods
Triple Negative Breast Neoplasms* / metabolism
Triple Negative Breast Neoplasms* / pathology

Substances

Histones
Biomarkers, Tumor
Proteome
Lysine

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the Provincial Natural Science Fund of Fujian (Grant number: 2021J01444), the Joint Funds for the Innovation of Science and Technology, Fujian province (Grant number: 2021Y9222), and the First Batch of High-level Talent Training Program of Fujian Cancer Hospital (2022YNG18).