Deficiency of Ku Induces Host Cell Exploitation in Human Cancer Cells.

Okay Saydam,Nurten Saydam

doi:10.3389/fcell.2021.651818

Okay Saydam, Nurten Saydam

Open Access

https://doi.org/10.3389/fcell.2021.651818

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Abstract

Cancer metastasis is the major cause of death from cancer (Massague and Obenauf, 2016; Steeg, 2016). The extensive genetic heterogeneity and cellular plasticity of metastatic tumors set a prime barrier for the current cancer treatment protocols (Boumahdi and de Sauvage, 2020). In addition, acquired therapy resistance has become an insurmountable obstacle that abolishes the beneficial effects of numerous anti-cancer regimens (De Angelis et al., 2019; Boumahdi and de Sauvage, 2020). Here we report that deficiency of Ku leads to the exploitation of host cells in human cancer cell line models. We found that, upon conditional deletion of XRCC6 that codes for Ku70, HCT116 human colorectal cancer cells gain a parasitic lifestyle that is characterized by the continuous cycle of host cell exploitation. We also found that DAOY cells, a human medulloblastoma cell line, innately lack nuclear Ku70/Ku86 proteins and utilize the host-cell invasion/exit mechanism for maintenance of their survival, similarly to the Ku70 conditionally-null HCT116 cells. Our study demonstrates that a functional loss of Ku protein promotes an adaptive, opportunistic switch to a parasitic lifestyle in human cancer cells, providing evidence for a previously unknown mechanism of cell survival in response to severe genomic stress. We anticipate that our study will bring a new perspective for understanding the mechanisms of cancer cell evolution, leading to a shift in the current concepts of cancer therapy protocols directed to the prevention of cancer metastasis and therapy resistance.

Highlights

Tumor cell plasticity is a key challenge for current cancer therapy (Boumahdi and de Sauvage, 2020)
We investigated the cellular dynamics of a human colorectal cancer cell line (HCT116) that is engineered for conditional deletion of XRCC6 gene (Fattah et al, 2008) by using live-cell imaging and confocal microscopy technologies
To be able to track actively moving cells, the nuclei of Ku70f/− cells were labeled by using the lentiviral H2B-EGFP or H2B-mRFP reporters, and the cell membranes of Ku70f/− cells were labeled by the membrane-targeted EGFP (Palm-EGFP) or tdTomato (PalmtdTomato) reporters that are fused to a palmitoylation signal (Palm) (Liu et al, 1994; Lai et al, 2015)

Summary

Introduction

Tumor cell plasticity is a key challenge for current cancer therapy (Boumahdi and de Sauvage, 2020). Understanding the processes yielding profound genetic diversity within the same tumor, as well as between the primary and metastatic pairs is a fundamental issue and of immediate research interest while cancer cell metastasis and drug resistance are winning out and offsetting the current cancer therapy protocols at large. Ku70/Ku86 heterodimer is best characterized for its ability to recognize and bind the broken ends of double-strand DNA (Walker et al, 2001). The functional importance of Ku resides in its key role in the non-homologous end joining (NHEJ) repair of DNA double-strand breaks (DSBs), and in the protection of telomeres (Fell and Schild-Poulter, 2015). While Ku is not essential for organismal development in mice (Nussenzweig et al, 1996; Zhu et al, 1996; Gu et al, 1997; Nussenzweig et al, 1997; Manis et al, 1998), its function has been reported to be critical for the maintenance of genome integrity and cell survival in humans (Li et al, 2002; Fattah et al, 2008)

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