Targeting Chromatin-Remodeling Factors in Cancer Cells: Promising Molecules in Cancer Therapy

Zhang, Fang-Lin; Li, Da‐Qiang

doi:10.3390/ijms232112815

Cited by 12 publications

(8 citation statements)

References 223 publications

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“…The role of CHAF1A in anti-cancer immunity remains unclear. Recently, regulators similar to CHAF1A in chromatin organization and remodeling have been reported to play critical roles in anticancer immunity, and have therefore become promising targets for cancer treatment [ 30 , 31 ]. Our GSEA showed that CHAF1A was associated with many DNA repair and metabolic pathways.…”

Section: Discussionmentioning

confidence: 99%

A novel biomarker associated with EBV infection improves response prediction of immunotherapy in gastric cancer

Li,

Xiong,

et al. 2024

J Transl Med

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Background Novel biomarkers are required in gastric cancer (GC) treated by immunotherapy. Epstein-Barr virus (EBV) infection induces an immune-active tumor microenvironment, while its association with immunotherapy response is still controversial. Genes underlying EBV infection may determine the response heterogeneity of EBV + GC. Thus, we screened hub genes associated with EBV infection to predict the response to immunotherapy in GC. Methods Prognostic hub genes associated with EBV infection were screened using multi-omic data of GC. EBV + GC cells were established and confirmed by EBV-encoded small RNA in situ hybridization (EBER-ISH). Immunohistochemistry (IHC) staining of the hub genes was conducted in GC samples with EBER-ISH assay. Infiltrating immune cells were stained using immunofluorescence. Results CHAF1A was identified as a hub gene in EBV + GC, and its expression was an independent predictor of overall survival (OS). EBV infection up-regulated CHAF1A expression which also predicted EBV infection well. CHAF1A expression also predicted microsatellite instability (MSI) and a high tumor mutation burden (TMB). The combined score (CS) of CHAF1A expression with MSI or TMB further improved prognostic stratification. CHAF1A IHC score positively correlated with the infiltration of NK cells and macrophages M1. CHAF1A expression alone could predict the immunotherapy response, but its CS with EBV infection, MSI, TMB, or PD-L1 expression showed better effects and improved response stratification based on current biomarkers. Conclusions CHAF1A could be a novel biomarker for immunotherapy of GC, with the potential to improve the efficacy of existing biomarkers.

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Section: Discussionmentioning

confidence: 99%

A novel biomarker associated with EBV infection improves response prediction of immunotherapy in gastric cancer

Li,

Xiong,

et al. 2024

J Transl Med

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“…There are ongoing developments in drugs that target genomic abnormalities of CRFs and combination therapies aimed at enhancing the therapeutic effects of anticancer drugs (41). In a previous study, the histone deacetylase inhibitor romidepsin, which targets CHD4, was demonstrated to suppress the progression of metastases in ovarian cancer both in vitro and in vivo (42).…”

Section: Discussionmentioning

confidence: 99%

Gene amplification of chromatin remodeling factor SMARCC2 and low protein expression of ACTL6A are unfavorable factors in ovarian high‑grade serous carcinoma

Magarifuchi,

Iwasaki,

Katayama

et al. 2024

Oncol Lett

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Ovarian high-grade serous carcinoma (OHGSC) is the most common type of ovarian cancer worldwide. Genome sequencing has identified mutations in chromatin remodeling factors (CRFs) in gynecological cancer, such as clear cell carcinoma, endometrioid carcinoma and endometrial serous carcinoma. However, to the best of our knowledge, the association between CRFs and OHGSC remains unexplored. The present study aimed to investigate the clinicopathological and molecular characteristics of CRF dysfunction in OHGSC. CRF alterations were analyzed through numerous methods, including the analysis of public next-generation sequencing (NGS) data from 585 ovarian serous carcinoma cases from The Cancer Genome Atlas (TCGA), immunohistochemistry (IHC), and DNA copy number assays, which were performed on 203 surgically resected OHGSC samples. In the public NGS dataset, the most frequent genetic alteration was actin-like protein 6A (ACTL6A) amplification at 19.5%. Switch/sucrose non-fermentable related, matrix associated, actin dependent regulator of chromatin subfamily c member 2 (SMARCC2) amplification (3.1%) was associated with significantly decreased overall survival (OS). In addition, chromodomain-helicase-DNA-binding protein 4 (CHD4) amplification (5.7%) exhibited unfavorable outcome trends, although not statistically significant. IHC revealed the protein expression loss of ARID1A (2.5%), SMARCA2 (2.5%) and SMARCA4 (3.9%). The protein expression levels of ACTL6A, SMARCC2 and CHD4 were evaluated using H-score. Patients with low protein expression levels of ACTL6A showed a significantly decreased OS. Copy number gain or gene amplification was demonstrated in ACTL6A (66.2%) and SMARCC2 (33.5%), while shallow deletion or deep deletion was demonstrated in CHD4 (70.7%). However, there was no statistically significant difference in protein levels of these CRFs, between the different copy number alterations (CNAs). Overall, OHGSC exhibited CNAs and protein loss, indicating possible gene alterations in CRFs. Moreover, there was a significant association between the protein expression levels of ACTL6A and poor prognosis. Based on these findings, it is suggested that CRFs could serve as prognostic markers for OHGSC.

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“…We focus on chromatin remodeling in GI cancer as it has been recently revisited as an important disease modulator and therapeutic target by us and other researchers [ 14 , 15 ]. For the storage of genetic information, chromatin is composed of the nucleosome, which contains DNA and histones [ 15 , 16 ], and for proper regulation of gene expression, nucleosomes are modulated by a chromatin remodeling complex in an ATP-dependent manner [ 16 , 17 ]. These chromatin remodeling complexes include switch/sucrose non-fermentable (SWI/SNF), initiator of SWI (ISWI), chromodomain helicase DNA binding protein (CHD), and INO80 [ 16 ], which are frequently mutated and participate in tumorigenesis in GI cancers.…”

Section: Introductionmentioning

confidence: 99%

Chromatin Remodeling-Related PRDM1 Increases Stomach Cancer Proliferation and Is Counteracted by Bromodomain Inhibitor

Hung,

Wang,

Pan

et al. 2024

JPM

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Gastrointestinal (GI) cancers are some of the main public health threats to the world. Even though surgery, chemotherapy, and targeted therapy are available for their treatments, these approaches provide limited success in reducing mortality, making the identification of additional therapeutic targets mandatory. Chromatin remodeling in cancer has long been studied and related therapeutics are widely used, although less is known about factors with prognostic and therapeutic potential in such areas as gastrointestinal cancers. Through applying systematic bioinformatic analysis, we determined that out of 31 chromatin remodeling factors in six gastrointestinal cancers, only PR/SET domain 1 (PRDM1) showed both expression alteration and prognosis prediction. Analyses on pathways, therapies, and mediators showed that cell cycle, bromodomain inhibitor IBET151, and BET protein BRD4 were, respectively involved in PRDM1-high stomach cancer, while cell line experiments validated that PRDM1 knockdown in human stomach cancer cell line SNU-1 decreased its proliferation, BRD4 expression, and responsiveness to IBET151; accordingly, these results indicate the contribution by PRDM1 in stomach cancer formation and its association with BRD4 modulation as well as BET inhibitor treatment.

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Targeting Chromatin-Remodeling Factors in Cancer Cells: Promising Molecules in Cancer Therapy

Cited by 12 publications

References 223 publications

A novel biomarker associated with EBV infection improves response prediction of immunotherapy in gastric cancer

A novel biomarker associated with EBV infection improves response prediction of immunotherapy in gastric cancer

Gene amplification of chromatin remodeling factor SMARCC2 and low protein expression of ACTL6A are unfavorable factors in ovarian high‑grade serous carcinoma

Chromatin Remodeling-Related PRDM1 Increases Stomach Cancer Proliferation and Is Counteracted by Bromodomain Inhibitor

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