The cell cycle machinery controls cell proliferation and the dysregulation of the cell cycle lies at the heart of carcinogenesis. Thus, exploring the unknown regulators involved in the cell cycle not only contribute to better understanding of cell proliferation but also provide substantial improvement to cancer therapy. In this study, we identified that the expression of methyltransferase METTL3 was upregulated in the M phase. Overexpression of METTL3 facilitated cell cycle progression, induced cell proliferation
in vitro
and enhanced tumorigenicity
in vivo
, while knockdown of METTL3 reversed these processes. METTL3 induced
CDC25B
mRNA m
6
A modification in the M phase, which accelerated the translation of
CDC25B
mRNA through YTHDF1-dependent m
6
A modification. Clinical data analysis showed that METTL3 and CDC25B were highly expressed in cervical cancer. Our work reveals that a new mechanism regulates cell cycle progression through the METTL3/m
6
A/CDC25B pathway, which provides insight into the critical roles of m
6
A methylation in the cell cycle.
Ferroptosis has been implicated in the therapeutic responses of various types of tumors. Cyclophosphamide (CTX), one of the most successful antitumor agents, is widely used to treat both hematopoietic and solid tumors. In this study, we revealed the ferroptosis pathway targeted by CTX treatment in tumor cells and clarified its mechanisms. Cell viability was remarkably suppressed by CTX, accompanied by the accumulation of intracellular iron and reactive oxygen species (ROS), reduced glutathione levels, deformed mitochondria and a loss of the mitochondrial membrane potential. These effects were impeded by the ferroptosis inhibitors ferrostatin-1 (Fer1) and deferoxamine (DFO). Moreover, CTX treatment obviously upregulated nuclear factor E2 related factor 2 (NRF2) and heme oxygenase-1 (HMOX-1) expression. Additionally, the HMOX-1 inducer Hemin notably enhanced CTX-mediated tumor inhibition in vitro and in vivo through a mechanism that involved interfering with the ferroptosis process. Therefore, our findings indicated ferroptosis induction by CTX through the activation of the NRF2/HMOX-1 pathway, which might provide a potential strategy for tumor chemotherapy.
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