Study on the Pro-Cancer Mechanism and Application Value of NCAPD3 in Diffuse Large B-Cell Lymphoma

Academic Background

Diffuse large B-cell lymphoma (DLBCL) is the most common hematological malignancy, characterized by significant clinical and biological heterogeneity. Although advances in treatment have been made in recent years, a subset of patients still have poor prognoses, especially those with chromosomal instability (CIN). Chromosomal instability is a critical biological basis for tumor initiation and progression and is widely present in lymphoma. However, the specific mechanisms of chromosomal instability in DLBCL remain unclear.

Condensin, a structural maintenance of chromosome complex, is an important molecular motor protein for chromosome assembly, compaction, and segregation. Its role in chromosome dynamics has been extensively studied. NCAPD3, a subunit of condensin II, plays a dominant role in chromosome axial compaction, but its function in lymphoma has not been thoroughly investigated. Based on the importance of NCAPD3 in chromosome structural stability and the prevalence of CIN in DLBCL, this study aims to explore the function and mechanism of NCAPD3 in DLBCL, particularly its role in chromatin remodeling and transcriptional regulation.

Source of the Paper

This study was co-authored by Tiange Lu, Juan Yang, and other researchers from the Department of Hematology at Shandong Provincial Hospital Affiliated with Shandong University, the National Cancer Center, and other institutions. The paper was published in 2025 in the Journal of Advanced Research (Volume 68, Pages 163–178), titled “NCAPD3 Promotes Diffuse Large B-Cell Lymphoma Progression Through Modulating SIRT1 Expression in an H3K9 Monomethylation-Dependent Manner.” The research reveals the pro-cancer mechanism of NCAPD3 in DLBCL and proposes potential therapeutic targets.

Research Process and Results

1. Expression and Clinical Significance of NCAPD3 in DLBCL

Subjects: Through public databases and clinical samples, the researchers analyzed lymph node specimens from 70 DLBCL patients and 35 patients with reactive lymph node hyperplasia (RHL), as well as peripheral blood mononuclear cells (PBMCs) from healthy donors.

Methods: Immunohistochemistry (IHC) was used to detect NCAPD3 expression, and gene expression profile analysis was performed to assess its expression levels in DLBCL.

Results: NCAPD3 was significantly overexpressed in DLBCL samples and was significantly associated with shorter overall survival (OS) in patients (p=0.0067). IHC staining further confirmed that the positive rate of NCAPD3 in DLBCL tissues was as high as 77%, compared to only 11.4% in RHL. These results suggest that NCAPD3 may serve as a prognostic marker for DLBCL.

2. The Impact of NCAPD3 on DLBCL Cell Growth

Subjects: DLBCL cell lines (OCI-LY1, OCI-LY8, U2932) and normal CD19+ B lymphocytes.

Methods: NCAPD3 knockout and overexpression cell lines were constructed using CRISPR/Cas9 technology. Cell proliferation was assessed by CCK-8 assay, and flow cytometry was used to analyze apoptosis and cell cycle.

Results: NCAPD3 knockout significantly inhibited DLBCL cell proliferation and induced apoptosis, while overexpression accelerated cell proliferation. Additionally, NCAPD3 deletion led to loose chromosome structures and increased aneuploid formation. These results further confirm the important role of NCAPD3 in chromosome dynamics.

3. The Effect of NCAPD3 on Drug Sensitivity

Methods: The sensitivity of DLBCL cells with different NCAPD3 expression levels to doxorubicin and ibrutinib was tested.

Results: NCAPD3 knockout significantly increased the sensitivity of DLBCL cells to doxorubicin and ibrutinib, indicating that NCAPD3 may serve as a potential target for combination therapy.

4. In Vivo Function of NCAPD3

Subjects: Severe combined immunodeficiency (SCID) mouse models.

Methods: NCAPD3 knockout and control OCI-LY1 cells were subcutaneously injected into mice to observe tumor growth.

Results: NCAPD3 knockout significantly suppressed DLBCL tumor growth, and the proliferation marker Ki-67 expression was reduced in tumor tissues. This further validates the pro-cancer role of NCAPD3 in DLBCL.

5. Transcriptional Regulatory Mechanism of NCAPD3

Methods: Mass spectrometry (MS) was used to identify NCAPD3-interacting proteins, and chromatin immunoprecipitation (ChIP) assays were performed to validate its interactions with transcription factors and histone modifications.

Results: NCAPD3 interacts with transcription factor TFII I, anchors at the SIRT1 promoter, and regulates SIRT1 transcription by recognizing H3K9 monomethylation (H3K9me1) modifications. Functional reversion experiments further confirmed that the pro-cancer effect of NCAPD3 is partially mediated by SIRT1.

Conclusions and Significance

This study is the first to reveal the pro-cancer mechanism of NCAPD3 in DLBCL, demonstrating that NCAPD3 promotes DLBCL progression by regulating chromosome compaction and transcriptional activity. Specifically, NCAPD3 regulates SIRT1 expression through interactions with transcription factor TFII I and histone modification H3K9me1, thereby influencing DLBCL proliferation and drug sensitivity. This discovery not only provides new insights into the pathogenesis of DLBCL but also offers a theoretical basis for developing targeted therapies against NCAPD3.

Research Highlights

1. First to uncover the function of NCAPD3 in DLBCL, highlighting its potential as an oncogene and prognostic marker.
2. Proposed a novel mechanism by which NCAPD3 regulates SIRT1 transcription in an H3K9me1-dependent manner, providing a new perspective for transcriptional regulation research.
3. Validated the anti-tumor effects of targeting NCAPD3 through in vivo and in vitro experiments, offering new therapeutic targets for DLBCL.
4. Combined public database and clinical sample analysis, enhancing the reliability and clinical significance of the findings.

Additional Valuable Information

This study was supported by multiple projects, including the National Natural Science Foundation of China and the Key Research and Development Program of Shandong Province, reflecting its potential value in clinical applications. Moreover, the research team’s extensive expertise in chromosome dynamics and transcriptional regulation laid a solid foundation for the success of this study.