Impaired DNA double‐strand breaks repair by kinesin family member 4A inhibition renders human H1299 non‐small‐cell lung cancer cells sensitive to cisplatin

Abstract

Patients with non‐small‐cell lung cancer (NSCLC) are routinely treated with the platinum‐based chemotherapeutics such as cisplatin. The drug exerts anticancer effects via multiple mechanisms, including DNA double‐strand breaks (DSBs). Enhanced DNA DSB repair capacity would be associated with innate or acquired drug resistance. However, despite strong evidence for the role of the chromokinesin kinesin family member 4A (KIF4A) in DSB repair, the relationship between the chromokinesin and cisplatin sensitivity of human NSCLC cells remains unknown. Furthermore, little is known regarding the effect of targeting KIF4A on the function of DSB repair‐related proteins in these cells. In the current study, we demonstrated that cisplatin treatment stimulated the expression of KIF4A protein in human NSCLC cells. Depletion of KIF4A by small interfering RNA significantly enhanced cisplatin‐induced cell cycle arrest in S and G2/M phases and cytotoxicity in human NSCLC cells. Furthermore, we found that KIF4A inhibition suppressed the ability of cisplatin to induce BRCA2 and Rad51 focus formation and limits the further increase in poly(ADP‐ribose) polymerase 1 activity induced by cisplatin treatment in human NSCLC cells. These studies thus identify the chromokinesin KIF4A as a novel modulator of cisplatin sensitivity that is significantly enhanced by the chromokinesin in human NSCLC cells via multiple mechanisms.

<p>KIF4A Promotes Clear Cell Renal Cell Carcinoma (ccRCC) Proliferation in vitro and in vivo</p>

“…13 KIF4A also associates with the regulation of DSB repair-related proteins. 14 In recent years, the key role of KIF4A in cancer development has gradually been revealed. 15 KIF4A is widely expressed in a variety of human tissues.…”

The Kinesin Superfamily Handbook

“…This role for KIF4A in DNA repair underlies its effect as a modulator of sensitivity to the anticancer therapy cisplatin, which acts, among other mechanisms, by inducing DNA double-strand breaks. Cisplatin treatment is shown to stimulate expression of KIF4A in non-small-cell lung cancer cell lines, with depletion of KIF4A enhancing sensitivity to the cytotoxic effect of cisplatin via inhibition of the formation of BRCA2/Rad51 DNA repair foci (Wan et al 2019).…”

“…Two different mechanisms have been described for the impact of KIF4 expression on drug resistance in cancers. Overexpression of KIF4A results in resistance to doxorubin in breast cancer cell lines via suppression of apoptosis by inhibiting the activity of PARP-1 (Wang et al 2014), whilst resistance of lung cancer cell lines to cisplatin is mediated via upregulation of DNA repair mechanisms by KIF4A (Wan et al 2019). Bioinformatic analysis of available data on the expression of KIF4A in breast cancer suggests that KIF4A may be a strong prognostic biomarker for breast cancer and a promising therapeutic target (Xue et al 2018).…”

The nuclear kinesin KIF18B promotes 53BP1-mediated DNA double-strand break repair

“…In budding yeast, the kinesin-14 complex has been implicated with chromatin remodelers in break-induced recombination (BIR) at the nuclear pore (Chung et al, 2015). Previously, human KIF4A was reported to associate with BRCA2 and is proposed to regulate RAD51-and homology-dependent repair (Wu et al, 2008;Wan et al, 2019). More recently, KIF2C, also known as MCAK, was identified by virtue of its DNA-end-binding activity (Zhu et al, 2020).…”