International Journal of Medical Sciences
·
2022
·
IF 3.642
Zuofei Chi,Bin Zhang,Ruowen Sun,Ye Wang,Linlin Zhang,Gang Xu
T-cell acute lymphoblastic leukemia (T-ALL) is a common hematologic malignancy. Based on the data from {"type":"entrez-geo","attrs":{"text":"GSE66638","term_id":"66638"}} GSE66638 and {"type":"entrez-geo","attrs":{"text":"GSE141140","term_id":"141140"}} GSE141140 , T-ALL patients depicted a higher USP44 level. However, its role in T-ALL is still unclear. In the present study, we investigated the role of USP44 in T-ALL growth. USP44 overexpression elevated the proliferation of CCRF-CEM cells, while USP44 knockdown suppressed the proliferation of Jurkat and MOLT-4 cells. In addition, USP44 accelerated the cell cycle progression, with boosted cyclinD and PCNA levels. However, USP44 knockdown induced apoptosis in Jurkat and MOLT-4 cells, with an upheaval among cleaved caspase-3 and PARP levels. Mechanistically, USP44 co-localized and interacted with WDR5, leading to the repression of its ubiquitination and degradation. Interestingly, WDR5 overexpression abolished the apoptosis induced by USP44 knockdown. Consistently, the in vivo study revealed that USP44 knockdown restricted the leukemic engraftments in the bone marrow and spleens and reduced the infiltration of T-ALL cells in the livers and lungs. In conclusion, this study indicated that USP44 enhanced the growth of T-ALL through interacting with WDR5 and repressing its ubiquitination. This study highlights the potential use of USP44 as a therapeutic target of T-ALL.
研究领域:
肿瘤学
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血液学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Guanlu Long,Xianghan Wang,Xin Chen,Sai Ma,Liangkui Sun,Zhengyu Jiang,Qidong You,Xiaoke Guo
Targeting the WDR5–MLL1 protein–protein interaction (PPI) is considered to be an effective approach for the treatment of MLL-rearranged leukemia. However, interfering with WDR5–MLL1 PPI reduces methylated H3K4 levels and induces a decline in acetylated H3 levels, which may contribute to the suboptimal cellular efficacy of WDR5 inhibitors. We observed that cotreatment with WDR5–MLL1 PPI and HDAC inhibitors augmented the antiproliferative effect in MV-4-11 cells. Thus, a series of dual-target inhibitors was developed by merging the pharmacophores of the WDR5 and HDAC inhibitors. Among the developed inhibitors, compound 32d displayed an 89-fold increase in antiproliferative efficacy and induced potent cell apoptosis by impeding the DNA damage repair signaling pathway. Furthermore, the administration of 30 mg/kg of compound 32d was well tolerated, inhibiting MV-4-11 xenograft growth by 87.1%. Our investigation established the therapeutic effectiveness of the developed WDR5–MLL1/HDAC dual-target inhibitor against acute myeloid leukemia, providing a valuable tool for further exploration of crosstalk between the two targets.
研究领域:
药理学
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肿瘤学
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分子生物学
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DOI
PubMed
高影响因子
PLOS BIOLOGY
·
2023
·Vol. 21
·期 9
·e3002256
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IF 9.8
Jiaojiao Hao,Jinsheng Huang,Chunyu Hua,Yan Zuo,Wendan Yu,Xiaojun Wu,Liren Li,Guoqing Xue,Xinyu Wan,Liyuan Ru,Ziyue Guo,Shilong Han,Wuguo Deng,Fei Lin,Wei Guo
The eradication of cancer stem cells (CSCs) with drug resistance confers the probability of local tumor control after chemotherapy or targeted therapy. As the main drug resistance marker, ABCG2 is also critical for colorectal cancer (CRC) evolution, in particular cancer stem–like traits expansion. Hitherto, the knowledge about the expression regulation of ABCG2, in particular its upstream transcriptional regulatory mechanisms, remains limited in cancer, including CRC. Here, ABCG2 was found to be markedly up–regulated in CRC CSCs (cCSCs) expansion and chemo–resistant CRC tissues and closely associated with CRC recurrence. Mechanistically, TOX3 was identified as a specific transcriptional factor to drive ABCG2 expression and subsequent cCSCs expansion and chemoresistance by binding to −261 to −141 segments of the ABCG2 promoter region. Moreover, we found that TOX3 recruited WDR5 to promote tri–methylation of H3K4 at the ABCG2 promoter in cCSCs, which further confers stem–like traits and chemoresistance to CRC by co–regulating the transcription of ABCG2. In line with this observation, TOX3, WDR5, and ABCG2 showed abnormal activation in chemo–resistant tumor tissues of in situ CRC mouse model and clinical investigation further demonstrated the comprehensive assessment of TOX3, WDR5, and ABCG2 could be a more efficient strategy for survival prediction of CRC patients with recurrence or metastasis. Thus, our study found that TOX3–WDR5/ABCG2 signaling axis plays a critical role in regulating CRC stem–like traits and chemoresistance, and a combination of chemotherapy with WDR5 inhibitors may induce synthetic lethality in ABCG2–deregulated tumors.
研究领域:
肿瘤学
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分子生物学
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癌症干细胞
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转录调控
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Shan Yu,Jinghui Yang,Rui Zhang,Yu Zhang,Xinyi Fei
Cerebral ischemia-reperfusion injury (CIRI) usually has a high mortality and disability rate, and inflammatory stimulation is an important risk factor for CIRI. ISL LIM Homeobox 1 (ISL1) is involved in the regulation of inflammatory response, and its role in CIRI progression has not been reported. Here, we established an animal model of transient middle cerebral artery occlusion/reperfusion (tMCAO/R) and found that ISL1 was up-regulated in the peri-infarct cortex of tMCAO/R mice (log 2 FC = 4.7, adj. p < 0.01) and improved neurological dysfunction and reduced infarct size. At the same time, we found that ISL1 suppressed the expression of proinflammatory markers in the peri-infarct cortex. Consistently, in an oxygen-glucose deprivation/reoxygenation (OGD/R)-induced microglial HMC3 cell model, ISL1 overexpression significantly curtailed the inflammatory response, as evidenced by reduced iNOS and CD16/32 expression. Mechanistically, dual-luciferase and ChIP assays confirmed that ISL1 promotes the transcriptional activation of Stanniocalcin 1 (STC1) by enhancing H3K4me3 enrichment at its promoter region. Furthermore, GST pull-down analyses suggested that this transcriptional regulation is likely mediated through the physical interaction between ISL1 and WDR5, which may recruit the MLL complex to facilitate H3K4me3 deposition. Collectively, our findings indicate that the ISL1-WDR5-H3K4me3 axis contributes to the upregulation of STC1, thereby attenuating neuroinflammation and CIRI-induced brain injury.
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产品关联
DOI
PubMed
高影响因子
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