Nucleolar and spindle associated protein 1 enhances chemoresistance through DNA damage repair pathway in chronic lymphocytic leukemia by binding with RAD51

Yang Han,Zheng Tian,Jiarui Liu,Juan Yang,Ya Zhang,Xin Wang,Xin Zhang,Xinting Hu,Xiaoya Yun

doi:10.1038/s41419-021-04368-2

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.

Highlights

Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia among the elderly in western countries featured by a heterogeneous clinical course and easy recurrence [1]
Our evidences identified that Nucleolar and spindle-associated protein 1 (NUSAP1) was elevated in CLL cells and specimens, which was related to poor prognosis of CLL patients
The suppression of NUSAP1 reduced the growth of CLL cells both in vivo and vitro, which enhanced the sensitivity of CLL cells to fludarabine and ibrutinib

Summary

Introduction

Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia among the elderly in western countries featured by a heterogeneous clinical course and easy recurrence [1]. Many genetic abnormalities are associated with refractory course, poor prognosis, and chemoresistance [2]. DNA damage is a recurring phenomenon and serves as a major factor in cancer development inducing normal cells to obtain oncogenic mutations [3]. Suppression of the DNA repair process is considered to be a promising approach for CLL treatment [4]. Nucleolar and spindle-associated protein 1 (NUSAP1), with a molecular weight of 55KD, serves as a microtubule-binding protein in chromosome separation, spindle assembly, and plays significant role to ensure normal regulation of cell cycle as well [5]. NUSAP1 engages in the biological process such as cell proliferation, apoptosis, cell cycle and metastasis in several types of cancers by regulating Wnt/β-catenin [12], Hedgehog [13], PI3K/AKT [14], Hippo-Yap1 [9], and other pathways. Its function and mechanism in the development of CLL remain elusive

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