Gui Anping, Cao Xiaoshan, Meng Fengjiao, Chen Yingzhi, Ma Shihui, Chen Hong
Breast Center, People's Hospital of Zhongshan City, Zhongshan, Guangdong 528400, P.R. China.
Department of Pathology, People's Hospital of Zhongshan City, Zhongshan, Guangdong 528400, P.R. China.
Oncol Lett. 2024 Nov 22;29(2):72. doi: 10.3892/ol.2024.14818. eCollection 2025 Feb.
Protein lactylation represents a pervasive post-translational modification prevalent in histones and diverse proteins, fostering tumor initiation and progression. Nonetheless, the impact of protein lactylation on the prognosis of non-specific triple-negative breast cancer (TNBC) remains uncertain. In the present study, the pan-lysine lactylation (panKlac) levels in cytoplasmic and nuclear compartments were semi-quantitatively examined using a tissue microarray encompassing 77 non-specific TNBC tissues. The association of the prognosis of patients with the panKlac levels in the cytoplasmic and nuclear compartments or other tumor attributes was assessed using Kaplan-Meier and Cox regression analyses. Furthermore, the molecular pathways involved in the promotional effect of lactylation on cell proliferation were determined through a transcriptomic analysis. The results indicated that the panKlac levels were markedly higher in tumor tissues than in para-tumor mammary regions and showed no significant correlations with various clinicopathological parameters, such as tumor dimension, lymph node involvement or histological grading. Notably, high panKlac levels within the nucleus served as an independent predictor of recurrence-free survival, whereas high cytoplasmic panKlac levels were a protective factor for patient survival. The panKlac levels were also markedly elevated in the TNBC cell line, MDA-MB-231. Additionally, glycolysis inhibition significantly reduced the global panKlac levels and concurrently diminished cell proliferation. According to the comprehensive transcriptomic analysis results, pathways related to ribosomal subunit biosynthesis/assembly and aminoacyl-tRNA biosynthesis were involved in the tumor-promoting mechanisms of lactylation. Further results revealed the oncogenic propensity of tyrosyl-tRNA synthetase 1 (YARS1) and its association with lactate production. Overall, Klac levels within the nucleus are an independent prognostic indicator for patients with non-specific TNBC. It is imperative to delve deeper into the roles and mechanisms of nuclear protein lactylation and YARS1 in non-specific TNBC.
蛋白质乳酰化是一种普遍存在的翻译后修饰，在组蛋白和多种蛋白质中都很常见，它促进肿瘤的发生和发展。然而，蛋白质乳酰化对非特异性三阴性乳腺癌（TNBC）预后的影响仍不确定。在本研究中，使用包含77个非特异性TNBC组织的组织微阵列，对细胞质和细胞核区室中的泛赖氨酸乳酰化（panKlac）水平进行了半定量检测。使用Kaplan-Meier和Cox回归分析评估了细胞质和细胞核区室中panKlac水平或其他肿瘤特征与患者预后的相关性。此外，通过转录组分析确定了乳酰化促进细胞增殖的分子途径。结果表明，肿瘤组织中的panKlac水平明显高于肿瘤旁乳腺区域，且与肿瘤大小、淋巴结受累情况或组织学分级等各种临床病理参数无显著相关性。值得注意的是，细胞核内高panKlac水平是无复发生存的独立预测指标，而细胞质中高panKlac水平是患者生存的保护因素。TNBC细胞系MDA-MB-231中的panKlac水平也明显升高。此外，糖酵解抑制显著降低了整体panKlac水平，并同时减少了细胞增殖。根据综合转录组分析结果，与核糖体亚基生物合成/组装和氨酰-tRNA生物合成相关的途径参与了乳酰化的肿瘤促进机制。进一步的结果揭示了酪氨酰-tRNA合成酶1（YARS1）的致癌倾向及其与乳酸产生的关联。总体而言，细胞核内的Klac水平是非特异性TNBC患者的独立预后指标。深入研究细胞核蛋白乳酰化和YARS1在非特异性TNBC中的作用和机制势在必行。
