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Published on: June 26, 2020
Nucleolar and spindle associated protein 1 enhances chemoresistance through DNA damage repair pathway in chronic
Yang Han1,2,3,4, Xinting Hu1,2,3,4, Xiaoya Yun1,2,3,4
1Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, China.
Abstract:
Nucleolar and spindle-associated protein 1 (NUSAP1) is an essential regulator of mitotic progression, spindle assembly, and chromosome attachment. Although NUSAP1 acts as an oncogene involved in the progression of several cancers, the exact role of chronic lymphocytic leukemia (CLL) remains elusive. Herein, we first discovered obvious overexpression of NUSAP1 in CLL associated with poor prognosis. Next, the NUSAP1 level was modulated by transfecting CLL cells with lentivirus. Silencing NUSAP1 inhibited the cell proliferation, promoted cell apoptosis and G0/G1 phase arrest. Mechanistically, high expression of NUSAP1 strengthened DNA damage repairing with RAD51 engagement. Our results also indicated that NUSAP1 knockdown suppressed the growth CLL cells in vivo. We further confirmed that NUSAP1 reduction enhanced the sensitivity of CLL cells to fludarabine or ibrutinib. Overall, our research investigates the mechanism by which NUSAP1 enhances chemoresistance via DNA damage repair (DDR) signaling by stabilizing RAD51 in CLL cells. Hence, NUSAP1 may be expected to be a perspective target for the treatment of CLL with chemotherapy resistance.
Insights
Nucleolar and spindle-associated protein 1 (NUSAP1) is overexpressed in chronic lymphocytic leukemia (CLL), promoting cancer growth and chemoresistance. Silencing NUSAP1 inhibits CLL cell proliferation and enhances treatment sensitivity.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Nucleolar and spindle-associated protein 1 (NUSAP1) is crucial for mitosis and chromosome attachment.
- NUSAP1 functions as an oncogene in various cancers, but its role in chronic lymphocytic leukemia (CLL) is not well understood.
Purpose of the Study:
- To investigate the role of NUSAP1 in CLL pathogenesis and its potential as a therapeutic target.
- To elucidate the mechanism by which NUSAP1 influences CLL cell behavior and chemoresistance.
Main Methods:
- NUSAP1 expression levels were analyzed in CLL patient samples.
- NUSAP1 was silenced in CLL cells using lentiviral transfection.
- Cell proliferation, apoptosis, cell cycle, and DNA damage repair were assessed.
- In vivo xenograft models were used to evaluate NUSAP1 knockdown effects.
- Sensitivity to chemotherapy drugs (fludarabine, ibrutinib) was tested.
Main Results:
- NUSAP1 was significantly overexpressed in CLL and correlated with poor prognosis.
- NUSAP1 silencing inhibited CLL cell proliferation, induced apoptosis, and caused G0/G1 phase arrest.
- High NUSAP1 expression enhanced DNA damage repair by stabilizing RAD51.
- NUSAP1 knockdown suppressed CLL tumor growth in vivo.
- Reduced NUSAP1 expression increased CLL cell sensitivity to fludarabine and ibrutinib.
Conclusions:
- NUSAP1 overexpression promotes CLL progression and chemoresistance by enhancing DNA damage repair via RAD51.
- NUSAP1 is a potential therapeutic target for overcoming chemotherapy resistance in CLL.
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