TMEM189 promotes breast cancer through inhibition of autophagy-regulated ferroptosis

Abstract

Breast cancer is a leading cause of tumor-related death among women around the world, but its pathogenesis is still unclear. Transmembrane protein 189 (TMEM189) is widely expressed in many types of tissues and plays a critical role in tumorigenesis partly through mediating cell death. However, its regulatory function on breast cancer progression and particularly the underlying mechanisms have not been fully understood. In the present study, we found that TMEM189 knockdown significantly reduced the proliferation of breast cancer cells, while its over-expression facilitated the proliferative capacity of tumor cells. The effects of TMEM189 to promote breast cancer were validated in the constructed xenograft mouse models. RNA-sequencing studies subsequently showed that TMEM189 deletion was closely associated with ferroptosis signaling pathway, accompanied with elevated lipid reactive oxygen species (ROS) accumulation, cellular ROS production, malondialdehyde (MDA) and the intracellular iron releases. However, GSH levels in breast cancer cells were highly impeded upon TMEM189 inhibition. Intriguingly, we found that TMEM189 knockdown-induced ferroptotic cell death was considerably abolished after autophagy inhibitor 3-MA co-treatment, as evidenced by the markedly decreased ROS generation and intracellular iron accumulation. Moreover, TMEM189 ablation strongly up-regulated LC3BII and transferrin receptor 1 (TfR1) expression levels in breast cancer cells, whereas down-regulated p62 and GPX4. Importantly, the expression changes of these molecules related to autophagy and ferroptosis were almost diminished in response to 3-MA exposure, along with restored cell proliferation. These findings suggested that TMEM189 could inhibit autophagy to mediate ferroptosis in breast cancer cells. Collectively, all our findings revealed the therapeutic potential of TMEM189 in the treatment of breast cancer.