Identification of the oncogenic role of centromere protein M in non-small cell lung cancer via CDC20/MYBL2/Wnt signaling pathways

Journal of Molecular Histology (2025) 56:144 https://doi.org/10.1007/s10735-025-10423-5 ORIGINAL PAPER Identification of the oncogenic role of centromere protein M in nonsmall cell lung cancer via CDC20/MYBL2/Wnt signaling pathways Ling Wu2 · Jun Li1 · Haoyu Wang1 · Xu Chang1 · Qinglong Kong1 Received: 29 July 2024 / Accepted: 16 September 2024 / Published online: 26 April 2025 © The Author(s) 2025 Abstract Lung cancer remains the most prevalent carcinoma with a high mortality rate, yet the underlying mechanisms driving pulmonary neoplasia and disease progression are not fully understood. In our study, we conducted a comprehensive analysis of the transcriptome profiles and clinicopathological characteristics of 515 patients diagnosed with non-small cell lung cancer (NSCLC) from the TCGA database. We identified a significant upregulation of centromere protein M (CENPM) in NSCLC tissues, which was positively correlated with poor prognosis. Furthermore, overexpression of CENPM markedly promoted cell proliferation and increased the tumorigenic potential of NSCLC cell lines (A549/NCI-H1299), leading to accelerated tumor progression and reduced survival time in tumor-bearing mice. Mechanistically, CENPM activated the Wnt/β-catenin signaling pathway via the cell division cycle 20 (CDC20)/MYB proto-oncogene-like 2 (MYBL2) axis. Inhibition of either Wnt signaling or the CDC20/MYBL2 axis attenuated the tumorigenic potential and proliferative effects induced by CENPM. Our findings underscore the critical role of CENPM in driving NSCLC development and suggest that CENPM could serve as a novel biomarker for predicting NSCLC progression in clinical settings. Graphical abstract CENPM stimulates the expression of the cell differentiation cycle protein CDC20, leading to the upregulation of MYBL2. Consequently, the CDC20/MYBL2 axis activates the pro-survival Wnt/β-catenin signaling pathway, enhancing the tumorigenic potential and proliferative characteristics of lung cancer cells. This study underscores the crucial role of CENPM in promoting NSCLC development through the CDC20/MYBL2 signaling pathway. Thus, CENPM may serve as a novel biomarker for predicting NSCLC progression in clinical settings. Ling Wu and Jun Li have contributed equally to this work. Qinglong Kong 1 Department of Thoracic Surgery, Affiliated Central Hospital of Dalian University of Technology, Dalian, China 2 Department of pharmacy, Affiliated Central Hospital of Dalian University of Technology, Dalian, China 13 144 Page 2 of 11 Journal of Molecular Histology (2025) 56:144 Keywords CENPM · Wnt signaling · CDC20 · MYBL2 Abbreviations PKI 14–22 amide, myristoylated PUN PNU-74654 KAAD KAAD-Cyclopamine NSCLC Non-small cell lung cancer TCGA The Cancer Genome Atlas Program CENPM Centromere Protein M CDC20 Cell Division Cycle 20 MYBL2 MYB Proto-Oncogene Like 2 CIN Chromosomal instability KEGG Kyoto Encyclopedia of Genes and Genomes PANE1 Proliferation associated nuclear element 1 NAC Nucleosome‑associated complex Introduction Lung cancer is the leading cause of cancer-related deaths worldwide, with approximately 2.2 million new cases diagnosed and 1.8 million deaths in 2020, accounting for nearly one-fifth (18.0%) of all cancer deaths (Rosell and Karachaliou 2015; de Groot et al. 2018; Thandra et al. 2021). NSCLC constitutes 85% of all lung carcinomas (Herbst et al. 2018). Despite significant advances in diagnosis and therapeutic approaches, NSCLC continues to have one of the poorest prognoses among cancers. Emerging research has focused on identifying actionable molecular alterations, leading to the ongoing evolution of targeted treatments. However, the majority of NSCLC patients still experience tumor recurrence or distant metastasis within five years of diagnosis, with a five-year overall survival rate of just 18.2% (Rotow and Bivona 2017). Therefore, identifying innovative 13 prognostic biomarkers and gaining a better understanding of the mechanisms underlying tumor progression are crucial for improving clinical diagnosis and developing novel therapeutic strategies for NSCLC. CENPM, also named as proliferation-associated nuclear element 1 (PANE1), is a component of CENPA nucleosome‑associated complex (NAC) (Qi et al. 2022; Liu et al. 2020). It plays a vital role in the assembly of kinetochore proteins, chromosome segregation, and mitotic progression. Aberrant function of CENPM can lead to chromosomal instability (CIN) (McKinley and Cheeseman 2016), a hallmark of cancer that contributes to aneuploidy and tumorigenesis (Pino and Chung 2010; Qi et al. 2022). Moreover, the proliferative characteristics of cancer cells is tightly correlated with mitosis and chromosome separation (Wassmann and Benezra 2001). Indeed, numerous studies have demonstrated that abnormal expression of the CENPA complex is observed in several tumor types. For instance, upregulation of CENPA has been shown to stimulate tumor progression in colorectal cancer (Tomonaga et al. 2003), and increasing evidence suggested that CENPF contributed to a poor prognosis in patients with breast cancer and nasopharyngeal carcinoma (Sun et al. 2016). However, the specific mechanisms by which the CENPA complex contributes to tumor progression remain unclear. Recently, CENPM has been investigated in various cancer types and has emerged as a novel prognostic marker in liver cancer, melanoma, breast cancer, and bladder cancer (Xiao et al. 2019; Liu et al. 2020; Tong et al. 2024). Despite these findings, the relationship between CENPM and NSCLC progression has been relatively unexplored. While some studies suggest that the CENPM gene may play a role in the development of lung Page 3 of 11 144 Journal of Molecular Histology (2025) 56:144 adenocarcinoma (Zhou et al. 2021), its specific function in NSCLC progression remains to be fully elucidated. Our study conducted an initial screening of CENPM transcriptome expression in 515 NSCLC patients, suggesting the clinical relevance of CENPM in patient samples, demonstrating that its expression was closely associated with distant metastasis and reduced survival time in NSCLC patients. Mechanistically, CENPM overexpression significantly enhanced NSCLC cell proliferation and tumorigenic potential both in vitro and in vivo through the activation of Wnt/β-catenin signaling via the CDC20/MYBL2 axis. Thus, our study underscores the critical role of CENPM in NSCLC development and suggests its potential as a novel prognostic biomarker and therapeutic target for NSCLC patients. granted by the Ethics Committee of the Affiliated Central Hospital of Dalian University of Technology. Materials and methods For tumorigenic potential assay, pre-treated cells were seeded in 6-well plates (500 cells/ well). Then cells were cultured with serum-free culture medium. After 10 days, cell colony formation was observed under the inverted optical microscope (Leica, Germany). Meanwhile, colonies were washed, and stained wi (...truncated)