HDACs alters negatively to the tumor immune microenvironment in gynecologic cancers

Miao, Yanqing; Tao, Kangjia; Xiao, Bing; Chu, Yifan; Ma, Ding; Huang, Xiaoyuan; Han, Yingyan; Ji, Tiantian

doi:10.1016/j.gene.2023.147704

Gene

2023

DOI: 10.1016/j.gene.2023.147704

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HDACs alters negatively to the tumor immune microenvironment in gynecologic cancers

Yanqing Miao

Kangjia Tao

Bing Xiao

et al.

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2024

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Cited by 2 publications

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“…Our study presents an analysis of 17 neddylation-related genes, embodying a wide spectrum of biological functions, notably in protein degradation and ubiquitination exemplified by PSMB8, PSMB9, PSMB10, F-box protein 41 (FBXO41), FBXO17, F-box and leucine-rich repeat protein 16 (FBXL16), FBXL8 [49][50][51][52][53][54][55], cell cycle regulation and apoptosis including baculoviral IAP repeat containing 5 (BIRC5), denticleless E3 ubiquitin protein ligase homolog (DTL) [56,57], immune response and inflammation mediated by PSMB8, PSMB9, PSMB10, and ubiquitin D (UBD) [58][59][60][61], as well as DNA repair and genomic stability with a pivotal contribution from DNA damage-binding protein 2 (DDB2) [62].…”

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confidence: 99%

Evaluating the Role of Neddylation Modifications in Kidney Renal Clear Cell Carcinoma: An Integrated Approach Using Bioinformatics, MLN4924 Dosing Experiments, and RNA Sequencing

Liu,

Wu,

Wang

et al. 2024

Pharmaceuticals

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Background: Neddylation, a post-translational modification process, plays a crucial role in various human neoplasms. However, its connection with kidney renal clear cell carcinoma (KIRC) remains under-researched. Methods: We validated the Gene Set Cancer Analysis Lite (GSCALite) platform against The Cancer Genome Atlas (TCGA) database, analyzing 33 cancer types and their link with 17 neddylation-related genes. This included examining copy number variations (CNVs), single nucleotide variations (SNVs), mRNA expression, cellular pathway involvement, and methylation. Using Gene Set Variation Analysis (GSVA), we categorized these genes into three clusters and examined their impact on KIRC patient prognosis, drug responses, immune infiltration, and oncogenic pathways. Afterward, our objective is to identify genes that exhibit overexpression in KIRC and are associated with an adverse prognosis. After pinpointing the specific target gene, we used the specific inhibitor MLN4924 to inhibit the neddylation pathway to conduct RNA sequencing and related in vitro experiments to verify and study the specificity and potential mechanisms related to the target. This approach is geared towards enhancing our understanding of the prognostic importance of neddylation modification in KIRC. Results: We identified significant CNV, SNV, and methylation events in neddylation-related genes across various cancers, with notably higher expression levels observed in KIRC. Cluster analysis revealed a potential trade-off in the interactions among neddylation-related genes, where both high and low levels of gene expression are linked to adverse prognoses. This association is particularly pronounced concerning lymph node involvement, T stage classification, and Fustat score. Simultaneously, our research discovered that PSMB10 exhibits overexpression in KIRC when compared to normal tissues, negatively impacting patient prognosis. Through RNA sequencing and in vitro assays, we confirmed that the inhibition of neddylation modification could play a role in the regulation of various signaling pathways, thereby influencing the prognosis of KIRC. Moreover, our results underscore PSMB10 as a viable target for therapeutic intervention in KIRC, opening up novel pathways for the development of targeted treatment strategies. Conclusion: This study underscores the regulatory function and potential mechanism of neddylation modification on the phenotype of KIRC, identifying PSMB10 as a key regulatory target with a significant role in influencing the prognosis of KIRC.

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confidence: 99%

Evaluating the Role of Neddylation Modifications in Kidney Renal Clear Cell Carcinoma: An Integrated Approach Using Bioinformatics, MLN4924 Dosing Experiments, and RNA Sequencing

Liu,

Wu,

Wang

et al. 2024

Pharmaceuticals

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The Epigenetic Modifiers HDAC2 and HDAC7 Inversely Associate with Cancer Stemness and Immunity in Solid Tumors

Maciejewski,

Giers,

Oleksiewicz

et al. 2024

IJMS

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Dysregulation of histone deacetylases (HDACs) is closely associated with cancer development and progression. Here, we comprehensively analyzed the association between all HDAC family members and several clinicopathological and molecular traits of solid tumors across 22 distinct tumor types, focusing primarily on cancer stemness and immunity. To this end, we used publicly available TCGA data and several bioinformatic tools (i.e., GEPIA2, TISIDB, GSCA, Enrichr, GSEA). Our analyses revealed that class I and class II HDAC proteins are associated with distinct cancer phenotypes. The transcriptomic profiling indicated that class I HDAC members, including HDAC2, are positively associated with cancer stemness, while class IIA HDAC proteins, represented by HDAC7, show a negative correlation to cancer stem cell-like phenotypes in solid tumors. In contrast to tumors with high amounts of HDAC7 proteins, the transcriptome signatures of HDAC2-overexpressing cancers are significantly enriched with biological terms previously determined as stemness-associated genes. Moreover, high HDAC2-expressing tumors are depleted with immune-related processes, and HDAC2 expression correlates with tumor immunosuppressive microenvironments. On the contrary, HDAC7 upregulation is significantly associated with enhanced immune responses, followed by enriched infiltration of CD4+ and CD8+ T cells. This is the first comprehensive report demonstrating robust and versatile associations between specific HDAC family members, cancer dedifferentiation, and anti-tumor immune statuses in solid tumors.

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HDACs alters negatively to the tumor immune microenvironment in gynecologic cancers

Cited by 2 publications

References 57 publications

Evaluating the Role of Neddylation Modifications in Kidney Renal Clear Cell Carcinoma: An Integrated Approach Using Bioinformatics, MLN4924 Dosing Experiments, and RNA Sequencing

Evaluating the Role of Neddylation Modifications in Kidney Renal Clear Cell Carcinoma: An Integrated Approach Using Bioinformatics, MLN4924 Dosing Experiments, and RNA Sequencing

The Epigenetic Modifiers HDAC2 and HDAC7 Inversely Associate with Cancer Stemness and Immunity in Solid Tumors

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