BATF2 reverses multidrug resistance of gastric cancer cells and centrosome clustering by suppressing ATM phosphorylation

Wei Yang, Jianlin Song, Lixia Jiang, Wenchuan Zhu, Jianxun Wang, Qi Huang, Jiawei Hu,  Rong Zeng,  Bian Wu

Abstract:

Chromosome instability (CIN) is a major contributor to drug resistance and recurrence. As a crucial mechanism of CIN, centrosome clustering has emerged as a promising therapeutic strategy. However, the roles and regulatory mechanisms of centrosome clustering in gastric cancer remain unclear. BATF2 was previously identified as a key modulator of multidrug resistance (MDR) in gastric cancer (GC). To examine the involvement of centrosome clustering in the mechanism by which BATF2 reverses MDR in GC, adriamycin (ADR)- and vincristine (VCR)-resistant cell lines, NCI-N87/ADR and NCI-N87/VCR, were used for investigations. Expression of BATF2 was downregulated in both drug-resistant cells, particularly in NCI-N87/ADR cells. Cells with BATF2 knockdown exhibited higher cell viability and lower apoptosis rates, and such changes were reversed by BATF2 overexpression. The enhanced centrosome clustering in cells transfected with sh-BATF2 was accompanied by increased KIFC1 expression, which was inhibited after BATF2 overexpression. BATF2 reversed MDR and inhibited centrosome clustering by inhibiting ATM phosphorylation, which was evidenced by ATM overexpression. Meanwhile, KU-60019, a specific inhibitor of ATM, could markedly reverse the pro-tumor effects of BATF2 knockdown. In conclusion, BATF2 is a potential target for reversing MDR in GC, and targeting KIFC1-related centrosome clustering by suppressing ATM phosphorylation is proposed as a key mechanism.