Downregulation of FoxM1 sensitizes nasopharyngeal carcinoma cells to cisplatin via inhibition of MRN-ATM-mediated DNA repair

Abstract

Chemoresistance is the primary obstacle in the treatment of locally advanced and metastatic nasopharyngeal carcinoma (NPC). Recent evidence suggests that the transcription factor forkhead box M1 (FoxM1) is involved in chemoresistance. Our group previously confirmed that FoxM1 is overexpressed in NPC. In this study, we investigated the role of FoxM1 in cisplatin resistance of the cell lines 5–8F and HONE-1 and explored its possible mechanism. Our results showed that FoxM1 and NBS1 were both overexpressed in NPC tissues based on data from the GSE cohort (GSE12452). Then, we measured FoxM1 levels in NPC cells and found FoxM1 was overexpressed in NPC cell lines and could be stimulated by cisplatin. MTT and clonogenic assays, flow cytometry, γH2AX immunofluorescence, qRT-PCR, and western blotting revealed that downregulation of FoxM1 sensitized NPC cells to cisplatin and reduced the repair of cisplatin-induced DNA double-strand breaks via inhibition of the MRN (MRE11-RAD50-NBS1)-ATM axis, which might be related to the ability of FoxM1 to regulate NBS1. Subsequently, we demonstrated that enhanced sensitivity of FoxM1 knockdown cells could be reduced by overexpression of NBS1. Taken together, our data demonstrate that downregulation of FoxM1 could improve the sensitivity of NPC cells to cisplatin through inhibition of MRN-ATM-mediated DNA repair, which could be related to FoxM1-dependent regulation of NBS1.

Suppression of Hepatocellular Carcinoma Progression through FOXM1 and EMT Inhibition via Hydroxygenkwanin-Induced miR-320a Expression

“…Previous studies found that FOXM1 dysregulation can cause abnormal cell proliferation, thereby leading to carcinogenesis; its overexpression has been observed in many types of cancer including lung, liver, breast, brain, and oral cancers [43][44][45][46]. Other than serving as a cancer-specific diagnostic marker, FOXM1 is also a key anticancer target [47,48]. The present study revealed that HGK could inhibit both FOXM1 mRNA and protein expression, and also suppressed its downstream signaling pathways.…”

Differential Expression and Alternative Splicing of Transcripts Associated With Cisplatin-Induced Chemoresistance in Nasopharyngeal Carcinoma

“…Several studies have confirmed that the aberrant expression of certain mRNAs is involved in NPC che more sistance. Peng et al (2019) showed that hypermethylation of ARNTL (encoding aryl hydrocarbon receptor nuclear translocator like) promotes NPC tumorigenesis and inhibits cisplatin sensitivity by activating CDK5 (cyclin (Li D. et al, 2019). Zhang et al found that Epstein-Barr virus (EBV) activation of ATR (ATM and Rad3related)-mediated DNA damage response might result in chemotherapy resistance to CDDP (DDP) and 5-FU (Fluorouracil) in NPC (Zhang B. et al, 2019).…”

MRE11-RAD50-NBS1 complex alterations and DNA damage response: implications for cancer treatment

“…It was reported that targeting MRN complex can halt cancer cell growth and migration [151] and sensitize tumor cells to cisplatin, indicating that genetic modulation of MRN complex might open new avenues for cancers treatment [152]. NBS patients with mutations in NBS1 gene are susceptible to malignancy.…”