1. BMP8A promotes survival and drug resistance via Nrf2/TRIM24 signaling pathway in clear cell renal cell carcinoma
- Author
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Daming Zhang, Xing-Yuan Wang, Cheng Zhang, Licheng Cai, Jian-Kun Yang, Kong-Bin Yang, Tengda Wang, Yipeng Yu, Si-Yu Cheng, and Wengang Jian
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Carcinogenesis ,Gene Expression ,Apoptosis ,As2O3 ,environment and public health ,Mice ,0302 clinical medicine ,Arsenic Trioxide ,Wnt Signaling Pathway ,Chemistry ,Wnt signaling pathway ,General Medicine ,respiratory system ,Prognosis ,Kidney Neoplasms ,Gene Expression Regulation, Neoplastic ,Oncology ,030220 oncology & carcinogenesis ,Bone Morphogenetic Proteins ,Phosphorylation ,Female ,Original Article ,Signal transduction ,Cell Survival ,NF-E2-Related Factor 2 ,Wnt pathway ,Mice, Nude ,Antineoplastic Agents ,Bone morphogenetic protein ,TRIM24 ,Nrf2 ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Carcinoma, Renal Cell ,Cell Proliferation ,Cell growth ,Original Articles ,medicine.disease ,Clear cell renal cell carcinoma ,BMP8A ,030104 developmental biology ,Drug Resistance, Neoplasm ,Cancer research ,Carrier Proteins ,Reactive Oxygen Species - Abstract
There is increasing evidence that bone morphogenetic proteins (BMP) are involved in the proliferation and drug tolerance of kidney cancer. However, the molecular mechanism of BMP8A in renal cell proliferation and drug tolerance is not clear. Here we showed that BMP8A was highly expressed in renal cell carcinoma, which suggests a poor prognosis of ccRCC. Promotion of cell proliferation and inhibition of apoptosis were detected by CCK‐8 assay, Trypan Blue staining, flow cytometry and bioluminescence. BMP8A promoted resistance of As2O3 by regulating Nrf2 and Wnt pathways in vitro and in vivo. Mechanistically, BMP8A enhanced phosphorylation of Nrf2, which, in turn, inhibited Keap1‐mediated Nrf2 ubiquitination and, ultimately, promoted nuclear translocation and transcriptional activity of Nrf2. Nrf2 regulates the transcription of TRIM24 detected by ChIP‐qPCR. BMP8A was highly expressed in ccRCC, which suggests a poor prognosis. BMP8A was expected to be an independent prognostic molecule for ccRCC. On the one hand, activated Nrf2 regulated reactive oxygen balance, and on the other hand, by regulating the transcription level of TRIM24, it was involved in the regulation of the Wnt pathway to promote the proliferation, invasion and metastasis of ccRCC and the resistance of As2O3. Taken together, our findings describe a regulatory axis where BMP8A promotes Nrf2 phosphorylation and activates TRIM24 to promote survival and drug resistance in ccRCC., BMP8A can promote Nrf2 phosphorylation and nuclear translocation to exert antioxidative stress and transcriptional activity. At the same time, Nrf2 acts as a transcription factor of TRIM24, promotes the expression of TRIM24, activates the Wnt pathway and increases chemotherapy tolerance.
- Published
- 2019