Knockdown of ZBTB11 impedes R‐loop elimination and increases the sensitivity to cisplatin by inhibiting DDX1 transcription in bladder cancer

Abstract

Introduction Bladder cancer (BC) is one of the most common malignant cancers, with poor prognosis and high incidence. Cisplatin is the standard chemotherapy for muscle invasive bladder cancer; however, chemotherapy resistance remains a major challenge. Moreover, oncogenic signalling and the specific mechanisms underlying cisplatin resistance in BC remain largely unclear Methods In this study, RT‐PCR, Western blot, immunofluorescence, and immunohistochemistry were used to measure gene and protein expression. Colony formation assay and flow cytometry were performed to evaluate the proliferation of BC cells. Gene set enrichment analysis was performed to identify the function in which ZBTB11 was involved. Luciferase and chromatin immunoprecipitation experiments were performed to determine the transcriptional regulation mechanism of ZBTB11. The effects of ZBTB11 on the malignant phenotypes of BC cells were examined in vitro and in vivo Results The results showed that ZBTB11 was remarkably upregulated in BC tissues, which was associated with poor prognosis in patients with BC. Furthermore, we found that knockdown of ZBTB11 remarkably inhibited the proliferation and tumorigenesis of BC cells by inducing apoptosis. Mechanistically, the knockdown of ZBTB11 transcriptionally inhibited DDX1 to suppress R‐loop clearance, resulting in DNA damage in BC cells. Importantly, the ZBTB11/DDX1 axis is required for the chemotherapy resistance of BC cells to cisplatin Conclusion Our findings not only reveal an underlying mechanism by which the ZBTB11/DDX1 axis promotes the tumorigenesis of BC but also provide a potential target for a combination strategy of cisplatin‐based chemotherapy for BC.

Oncoprotein SET-associated transcription factor ZBTB11 triggers lung cancer metastasis

“…Furthermore, the reduced expression of ZBTB11 by mi-548j upon chronic hepatitis B (CHB) infection was related to the blunted antiviral effect by impairing type I interferon production 31 . Downregulation of ZBTB11 was also observed in hepatocellular carcinoma 32 , whereas overexpression of ZBTB11 was reported in bladder cancer 33 and different types of leukemia 34 , 35 . More recently, ZBTB11 was reported to participate in the long noncoding RNA (lncRNA) DUBR-mediated migration and invasion of lung cancer cells, suggesting a potential role of ZBTB11 during lung cancer progression 36 .…”

Advances in preclinical assessment of therapeutic targets for bladder cancer precision medicine

“…A similar finding was reported about the transcription factor ZBTB11. Targeting ZBTB11 increased the sensitivity of bladder cell lines to cisplatin by inhibiting the transcription of the RNA helicase DDX1, leading to the accumulation of R-loops and subsequent cell death [ 7 ].…”