ABSTRACT Renal cell carcinoma (RCC) is a commonly occurring and considerable burden on public health. Although chemotherapy benefits patients with advanced RCC, sunitinib resistance leads to a poor prognosis. Ferroptosis is also involved in sunitinib resistance in RCC. PR domain‐containing protein 1 with a zinc finger domain (PRDM1) is a tumor regulator in many types of cancer. However, its biological function in RCC has not been reported. This study aimed to investigate the role of PRDM1 in ferroptosis and sunitinib resistance in RCC and explore the underlying mechanisms. Bioinformatics analysis was performed to analyze the expression of related genes in RCC. PRDM1‐silencing and overexpressing cells were constructed to confirm the role of PRDM1 in RCC in vitro. Our results showed that PRDM1 expression was markedly upregulated in RCC tissues and cell lines. PRDM1 knockdown significantly induced ferroptosis in RCC cells. Furthermore, knockdown of PRDM1 elevated the sensitivity of RCC cell lines to Mechanistically, PRDM1 directly bound to ESM1 and regulated its transcription. Subsequently, ESM1 overexpression reversed the effects of si‐PRDM1 on ferroptosis and sunitinib sensitivity in RCC cells, and these effects were mitigated by a PI3K inhibitor. Finally, PRDM knockdown exhibited anti‐tumor effects in a xenograft animal model. Taken together, our study shows that PRDM1 silencing promotes ferroptosis and sunitinib sensitivity by inhibiting ESM1 transcription and modulating PI3K/Akt signaling in RCC. Our findings thus provide novel insights for therapeutically targeting RCC.
Zhang et al. (Mon,) studied this question.