STAT5B Suppresses Ferroptosis by Promoting DCAF13 Transcription to Regulate p53/xCT Pathway to Promote Mantle Cell Lymphoma Progression.

IF 5.3 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Biologics : Targets & Therapy Pub Date : 2024-07-04 eCollection Date: 2024-01-01 DOI:10.2147/BTT.S461287

Wen Jun Zhang, Chong Ling Hu, Bing Ling Guo, Xi Ping Liang, Chao Yu Wang, Tao Yang

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Abstract

Objective: 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.

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STAT5B 通过促进 DCAF13 转录来抑制铁凋亡，从而调节 p53/xCT 通路，促进套细胞淋巴瘤的进展。

研究目的本研究旨在分析STAT5B通过促进DCAF13转录调控p53/xCT通路来抑制套细胞淋巴瘤（MCL）中铁细胞减少的机制：方法：利用基因表达谱交互式分析（Gene Expression Profiling Interactive Analysis，GEPIA，http://gepia.cancer-pku.cn/index.html）分析了MCL中STAT5B、DCAF13和高铁血症之间的相关性。分别检测了 STAT5B、DCAF13、p53 和 xCT 在 MCL 患者中的表达水平和配对相关性。为了证实 STAT5B 在 MCL 铁变态反应中的关键作用，研究人员沉默了 STAT5B。研究人员还考察了阻断细胞坏死、凋亡和铁变态反应对 STAT5B 抗 MCL 作用的影响。构建了 STAT5B 过表达和/或 DCAF13 沉默的细胞，以证实 DCAF13 参与了 STAT5B 调节 p53/xCT 通路。DCAF13过表达和MG132证实了对p53泛素化的调控。通过肿瘤裸鼠模型阐明了沉默DCAF13和MG132对STAT5B过表达对MCL的影响：结果：DCAF13在MCL中过表达，与STAT5B呈正相关，与p53呈负相关，与xCT呈正相关。抑制铁变态反应可减轻 siSTAT5B 对 MCL 的抑制作用，而抑制坏死和凋亡的作用则很小。沉默DCAF13可阻断STAT5B对p53/xCT和铁凋亡的调控。DCAF13 的变化和 MG132 的添加对 p53 mRNA 没有统计学意义上的显著影响。DCAF13 的升高导致 p53 蛋白水平下调，而 MG132 逆转了这种抑制作用。在动物模型中，STAT5B 对 MCL 有促进作用，并抑制铁变态反应。Silencing of DCAF13 blocked STAT5B inhibition of p53 and induction of xCT, GPX4, and GSH.Conclusion：结论：STAT5B通过促进DCAF13转录来调节p53/xCT通路，从而抑制铁变态反应，促进MCL进展。

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