SETD8, a frequently mutated gene in cervical cancer, enhances cisplatin sensitivity by impairing DNA repair

Wang, Xin; Cao, Chen; Tan, Xiangyu; Liao, Xueyao; Du, Xiaofang; Wang, Xueqian; Liu, Ting; Gong, Danni; Hu, Zheng; Tian, Xun

doi:10.1186/s13578-023-01054-y

Cited by 4 publications

(3 citation statements)

References 55 publications

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“…However, the role and the regulatory mechanism of SETD8 in ES remain unknown. In the current investigation, we observed that the expression of SETD8 was elevated in ES, corroborating prior findings that SETD8 is overexpressed across a spectrum of malignancies, including neuroblastoma [ 13 ], pancreatic carcinoma [ 12 ], cervical cancer [ 24 ], multiple myeloma [ 25 ], and colorectal cancer [ 14 ]. Additionally, our findings indicate a strong correlation between elevated SETD8 expression and reduced OS and EFS in patients with ES, underscoring the clinical relevance of SETD8 in this context.…”

Section: Discussionsupporting

confidence: 90%

SETD8 inhibits apoptosis and ferroptosis of Ewing’s sarcoma through YBX1/RAC3 axis

Chen,

Hu,

Xiong

et al. 2024

Cell Death Dis

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Ewing’s sarcoma (ES) represents a rare yet exceedingly aggressive neoplasm that poses a significant health risk to the pediatric and adolescent population. The clinical outcomes for individuals with relapsed or refractory ES are notably adverse, primarily attributed to the constrained therapeutic alternatives available. Despite significant advancements in the field, molecular pathology-driven therapeutic strategies have yet to achieve a definitive reduction in the mortality rates associated with ES. Consequently, there exists an imperative need to discover innovative therapeutic targets to effectively combat ES. To reveal the mechanism of the SETD8 (also known as lysine methyltransferase 5A) inhibitor UNC0379, cell death manners were analyzed with different inhibitors. The contributions of SETD8 to the processes of apoptosis and ferroptosis in ES cells were evaluated employing the histone methyltransferase inhibitor UNC0379 in conjunction with RNA interference techniques. The molecular regulatory mechanisms of SETD8 in ES were examined through the application of RNA sequencing (RNA-seq) and mass spectrometry-based proteomic analysis. Moreover, nude mouse xenograft models were established to explore the role of SETD8 in ES in vivo. SETD8, a sole nucleosome-specific methyltransferase that catalyzes mono-methylation of histone H4 at lysine 20 (H4K20me1), was found to be upregulated in ES, and its overexpression was associated with dismal outcomes of patients. SETD8 knockdown dramatically induced the apoptosis and ferroptosis of ES cells in vitro and suppressed tumorigenesis in vivo. Mechanistic investigations revealed that SETD8 facilitated the nuclear translocation of YBX1 through post-transcriptional regulatory mechanisms, which subsequently culminated in the transcriptional upregulation of RAC3. In summary, SETD8 inhibits the apoptosis and ferroptosis of ES cells through the YBX1/RAC3 axis, which provides new insights into the mechanism of tumorigenesis of ES. SETD8 may be a potential target for clinical intervention in ES patients.

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Section: Discussionsupporting

confidence: 90%

SETD8 inhibits apoptosis and ferroptosis of Ewing’s sarcoma through YBX1/RAC3 axis

Chen,

Hu,

Xiong

et al. 2024

Cell Death Dis

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“…The roles of SETD8 and SYMD2 in chemoresistance have been reported by various groups. For example, melphalan resistance in multiple myeloma, cisplatin resistance in cervical cancer, and docetaxel resistance in hepatocellular carcinoma were all associated with SETD8 [ 44 – 46 ]. Similarly, SYMD2 enhanced oxaliplatin resistance in SW620 CRC cells by inducing the expression of drug efflux transporters [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

5-Fluorouracil dose escalation generated desensitized colorectal cancer cells with reduced expression of protein methyltransferases and no epithelial-to-mesenchymal transition potential

FENECH,

MICALLEF,

BARON

2024

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Background Colorectal cancer (CRC) is one of the most frequently diagnosed cancers. In many cases, the poor prognosis of advanced CRC is associated with resistance to treatment with chemotherapeutic drugs such as 5-Fluorouracil (5-FU). The epithelial-to-mesenchymal transition (EMT) and dysregulation in protein methylation are two mechanisms associated with chemoresistance in many cancers. This study looked into the effect of 5-FU dose escalation on EMT and protein methylation in CRC. Materials and Methods HCT-116, Caco-2, and DLD-1 CRC cell lines were exposed to dose escalation treatment of 5-FU. The motility and invasive potentials of the cells before and after treatment with 5-FU were investigated through wound healing and invasion assays. This was followed by a Western blot which analyzed the protein expressions of the epithelial marker E-cadherin, mesenchymal marker vimentin, and the EMT transcription factor (EMT-TF), the snail family transcriptional repressor 1 (Snail) in the parental and desensitized cells. Western blotting was also conducted to study the protein expressions of the protein methyltransferases (PMTs), Euchromatic histone lysine methyltransferase 2 (EHMT2/G9A), protein arginine methyltransferase (PRMT5), and SET domain containing 7/9 (SETD7/9) along with the global lysine and arginine methylation profiles. Results The dose escalation method generated 5-FU desensitized CRC cells with distinct morphological features and increased tolerance to high doses of 5-FU. The 5-FU desensitized cells experienced a decrease in migration and invasion when compared to the parental cells. This was reflected in the observed reduction in E-cadherin, vimentin, and Snail in the desensitized cell lines. Additionally, the protein expressions of EHMT2/G9A, PRMT5, and SETD7/9 also decreased in the desensitized cells and global protein lysine and arginine methylation became dysregulated with 5-FU treatment. Conclusion This study showed that continuous, dose-escalation treatment of 5-FU in CRC cells generated 5-FU desensitized cancer cells that seemed to be less aggressive than parental cells.

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“…Primary or acquired resistance to chemotherapy is a major barrier to breast cancer treatment. The main reasons for chemotherapy failure include (a) inadequate pharmacokinetic properties of the drug [29]; (b) tumor cell-intrinsic factors, such as the expression of drug e ux pumps, altered cellular homeostasis, and glucose metabolism; and (c) the tumor microenvironment, characterized by hypoxia and acidosis [30]. The mechanism of docetaxel resistance in breast cancer is multifaceted.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of FBP1 expression by KMT5A through TWIST1 methylation is one of the mechanisms leading to chemoresistance in breast cancer

Peng,

Ma,

Chen

et al. 2024

Oncol Rep

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Purpose: Lysine methyltransferase 5A (KMT5A) is the sole mammalian enzyme known to catalyze the monomethylation of histone H4 lysine 20 and nonhistone proteins such as p53, which are involved in the occurrence and progression of many cancers. Our study aimed to determine the function of KMT5A in inducing docetaxel resistance in patients with breast carcinoma by evaluating glucose metabolism and the underlying mechanism involved.Methods: We examined the upregulation or downregulation of KMT5A-related proteins after KMT5A knockdown in breast cancer cells by Tandem Mass Tag proteomics. Through differential protein expression and pathway enrichment analysis, the upregulated key gluconeogenic enzyme fructose-1,6bisphosphatase 1 (FBP1) was found. Loss of FBP1 expression is closely related to the development and prognosis of cancers. A dual-luciferase reporter gene assay con rmed that KMT5A inhibited the expression of FBP1 and that overexpression of FBP1 could enhance the chemotherapeutic sensitivity to docetaxel through the suppression of KMT5A expression. The KMT5A inhibitor UNC0379 was used to verify that docetaxel resistance induced by KMT5A through the inhibition of FBP1 depended on the methylase activity of KMT5A. According to previous literature and interaction network structure, we found that KMT5A acts on the transcription factor TWIST1. Then, we veri ed that TWSIT1 promoted the expression of FBP1 by using dual-luciferase reporter gene experiments.Conclusion: KMT5A affects chemotherapy resistance by regulating the cell cycle and positively regulates glycolysis-mediated chemotherapy resistance by inhibiting the transcription of FBP1 in collaboration with TWIST1. KMT5A may be a potential therapeutic target for chemotherapy resistance in breast cancer.

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SETD8, a frequently mutated gene in cervical cancer, enhances cisplatin sensitivity by impairing DNA repair

Cited by 4 publications

References 55 publications

SETD8 inhibits apoptosis and ferroptosis of Ewing’s sarcoma through YBX1/RAC3 axis

SETD8 inhibits apoptosis and ferroptosis of Ewing’s sarcoma through YBX1/RAC3 axis

5-Fluorouracil dose escalation generated desensitized colorectal cancer cells with reduced expression of protein methyltransferases and no epithelial-to-mesenchymal transition potential

Inhibition of FBP1 expression by KMT5A through TWIST1 methylation is one of the mechanisms leading to chemoresistance in breast cancer

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