Biologics: Targets & Therapy (Jul 2024)
STAT5B Suppresses Ferroptosis by Promoting DCAF13 Transcription to Regulate p53/xCT Pathway to Promote Mantle Cell Lymphoma Progression
Abstract
Wen Jun Zhang,* Chong Ling Hu,* Bing Ling Guo, Xi Ping Liang, Chao Yu Wang, Tao Yang Department of Hematology Oncology, Chongqing University Cancer Hospital, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tao Yang, Department of Hematology Oncology, Chongqing University Cancer Hospital, No. 181, Hanyu Road, Shapingba District, Chongqing, 400030, People’s Republic of China, Tel +86-13527363925, Email [email protected]: The purpose of this study was to analyze the mechanism by which STAT5B inhibits ferroptosis in mantle cell lymphoma (MCL) by promoting DCAF13 transcriptional regulation of p53/xCT pathway.Methods: The correlations between STAT5B, DCAF13 and ferroptosis in MCL were analyzed using Gene Expression Profiling Interactive Analysis (GEPIA, http://gepia.cancer-pku.cn/index.html). The expression levels and pairwise correlations of STAT5B, DCAF13, p53 and xCT in MCL patients were detected, respectively. STAT5B was silenced to confirm their criticality in MCL ferroptosis. the effects of blocking necrosis, apoptosis and ferroptosis on the anti-MCL effects of STAT5B were examined. Cells with STAT5B overexpression and/or DCAF13 silencing were constructed to confirm the involvement of DCAF13 in the STAT5B-regulated p53/xCT pathway. The regulation of p53 ubiquitination was confirmed by DCAF13 overexpression and MG132. The effects of silencing DCAF13 and MG132 on STAT5B overexpression on MCL was clarified by a tumor-bearing nude mouse model.Results: DCAF13 was overexpressed in MCL and positively correlated with STAT5B, negatively correlated with p53, and positively correlated with xCT. Inhibition of ferroptosis alleviated the inhibitory effects of siSTAT5B on MCL, while inhibition of necrosis and apoptosis had few effects. Silencing of DCAF13 led to the blocking of STAT5B regulation of p53/xCT and ferroptosis. The changes in DCAF13 and the addition of MG132 did not have statistically significant effects on p53 mRNA. Elevation of DCAF13 resulted in downregulation of p53 protein levels, and this inhibition was reversed by MG132. In animal models, the promotion of MCL and the inhibition of ferroptosis by STAT5B. Silencing of DCAF13 blocked STAT5B inhibition of p53 and induction of xCT, GPX4, and GSH.Conclusion: STAT5B suppresses ferroptosis by promoting DCAF13 transcription to regulate p53/xCT pathway to promote MCL progression.Keywords: mantle cell lymphoma, STAT5B, DCAF13, ferroptosis
