Histone Deacetylase Inhibitors (HDACi) Promote KLF5 Ubiquitination and Degradation in Basal-like Breast Cancer

Kong, Yanjie; Ren, Wenlong; Fang, Huan; Shah, Naseer Ali; Shi, Yujie; You, Dingyun; Zhou, Chengang; Jiang, Dewei; Yang, Chunzhang; Liang, Hongjun; Liu, Wenjin; Wang, Luzhen; Gan, Wenxia; Xing, Wei; Li, Fubing; Li, Zhen; Chen, Ceshi; Xie, Ni

doi:10.7150/ijbs.65322

Cited by 13 publications

(8 citation statements)

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“…We focused on heterochromatin-modifying enzymes, using chemical and genetic manipulations. This strategy has been extensively used in other types of cells ( Zhang et al, 2019 ) ( Kong et al, 2022 ) ( Kopytko et al, 2021 ) ( Farahi et al, 2022 ) and in our lab on oocytes ( Wasserzug-Pash et al, 2022 ).…”

Section: Resultsmentioning

confidence: 99%

Pre-pubertal oocytes harbor altered histone modifications and chromatin configuration

Pash

Karavani

Reich

et al. 2023

Front. Cell Dev. Biol.

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Pre-pubertal oocytes are still dormant. They are arrested in a GV state and do not undergo meiotic divisions naturally. A multitude of molecular pathways are changed and triggered upon initiation of puberty. It is not yet clear which epigenetic events occur in oocytes upon pubertal transition, and how significant these epigenetic events may be. We evaluated epigenetic marker levels in mouse pre-pubertal and post-pubertal female oocytes. In addition, we evaluated H3K9me2 levels in human oocytes collected from fertility preservation patients, comparing the levels between pre-pubertal patients and post-pubertal patients. The chromatin structure shows a lower number of chromocenters in mouse post-pubertal oocytes in comparison to pre-pubertal oocytes. All heterochromatin marker levels checked (H3K9me2, H3K27me3, H4K20me1) significantly rise across the pubertal transition. Euchromatin markers vary in their behavior. While H3K4me3 levels rise with the pubertal transition, H3K27Ac levels decrease with the pubertal transition. Treatment with SRT1720 [histone deacetylase (HDAC) activator] or overexpression of heterochromatin factors does not lead to increased heterochromatin in pre-pubertal oocytes. However, treatment of pre-pubertal oocytes with follicle-stimulating hormone (FSH) for 24 h - changes their chromatin structure to a post-pubertal configuration, lowers the number of chromocenters and elevates their histone methylation levels, showing that hormones play a key role in chromatin regulation of pubertal transition. Our work shows that pubertal transition leads to reorganization of oocyte chromatin and elevation of histone methylation levels, thus advancing oocyte developmental phenotype. These results provide the basis for finding conditions for in-vitro maturation of pre-pubertal oocytes, mainly needed to artificially mature oocytes of young cancer survivors for fertility preservation purposes.

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Section: Resultsmentioning

confidence: 99%

Pre-pubertal oocytes harbor altered histone modifications and chromatin configuration

Pash

Karavani

Reich

et al. 2023

Front. Cell Dev. Biol.

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“…In this study, we sought to investigate the molecular profiles associated with intrinsic and acquired resistance to CDK4/6i in HR + /HER2- BC. We focused on the transcription factors YB-1 and KLF5 [ 19 , 20 ] to determine whether these proteins can play critical roles in CDK4/6i resistance. To further understand how molecules evolve during the development of CDK4/6i resistance, we carried out experiments on CDK4/6i-sensitive MCF7 cells to construct resistant strains, which were established by treatment with a 6-month dose of abemaciclib.…”

Section: Discussionmentioning

confidence: 99%

“…We sought to investigate the molecular profiles associated with intrinsic and acquired resistance to CDK4/6i in HR + /HER2- BC. We focused on the functions of the transcription factors YB-1 and KLF5 in previous studies [ 19 , 20 ]. The transcription factor YB-1 belongs to the cold-shock domain protein family and is an oncogenic transcription factor that regulates DNA transcription, DNA repair, and translation activation [ 21 – 23 ].…”

Section: Introductionmentioning

confidence: 99%

Upregulated PARP1 confers breast cancer resistance to CDK4/6 inhibitors via YB-1 phosphorylation

Quan,

Wu,

Xiong

et al. 2023

Exp Hematol Oncol

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Background Cyclic-dependent kinase (CDK) 4/6 kinases, as the critical drivers of the cell cycle, are involved in the tumor progression of various malignancies. Pharmacologic inhibitors of CDK4/6 have shown significant clinical prospects in treating hormone receptor-positive and human epidermal growth factor receptor-negative (HR + /HER2-) breast cancer (BC) patients. However, acquired resistance to CDK4/6 inhibitors (CDK4/6i), as a common issue, has developed rapidly. It is of great significance that the identification of novel therapeutic targets facilitates overcoming the CDK4/6i resistance. PARP1, an amplified gene for CDK4/6i-resistant patients, was found to be significantly upregulated during the construction of CDK4/6i-resistant strains. Whether PARP1 drives CDK4/6i resistance in breast cancer is worth further study. Method PARP1 and p-YB-1 protein levels in breast cancer cells and tissues were quantified using Western blot (WB) analysis, immunohistochemical staining (IHC) and immunofluorescence (IF) assays. Bioinformatics analyses of Gene Expression Profiling Interactive Analysis (GEPIA), Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE) datasets were applied to explore the relationship between YB-1/PARP1 protein levels and CDK4/6i IC50. Cell Counting Kit-8 (CCK-8) and crystal violet staining assays were performed to evaluate cell proliferation rates and drug killing effects. Flow cytometry assays were conducted to assess apoptosis rates and the G1/S ratio in the cell cycle. An EdU proliferation assay was used to detect the DNA replication ratio after treatment with PARP1 and YB-1 inhibitors. A ChIP assay was performed to assess the interaction of the transcription factor YB-1 and associated DNA regions. A double fluorescein reporter gene assay was designed to assess the influence of WT/S102A/S102E YB-1 on the promoter region of PARP1. Subcutaneous implantation models were applied for in vivo tumor growth evaluations. Results Here, we reported that PARP1 was amplified in breast cancer cells and CDK4/6i-resistant patients, and knockdown or inhibition of PARP1 reversed drug resistance in cell experiments and animal models. In addition, upregulation of transcription factor YB-1 also occurred in CDK4/6i-resistant breast cancer, and YB-1 inhibition can regulate PARP1 expression. p-YB-1 and PARP1 were upregulated when treated with CDK4/6i based on the WB and IF results, and elevated PARP1 and p-YB-1 were almost simultaneously observed during the construction of MCF7AR-resistant strains. Inhibition of YB-1 or PAPR1 can cause decreased DNA replication, G1/S cycle arrest, and increased apoptosis. We initially confirmed that YB-1 can bind to the promoter region of PARP1 through a ChIP assay. Furthermore, we found that YB-1 phosphorylated at S102 was crucial for PARP1 transcription according to the double fluorescein reporter gene assay. The combination therapy of YB-1 inhibitors and CDK4/6i exerted a synergistic antitumor effect in vitro and in vivo. The clinical data suggested that HR + /HER2- patients with low expression of p-YB-1/PARP1 may be sensitive to CDK4/6i in breast cancer. Conclusion These findings indicated that a ‘‘YB-1/PARP1’’ loop conferred resistance to CDK4/6 inhibitors. Furthermore, interrupting the loop can enhance tumor killing in the xenograft tumor model, which provides a promising strategy against drug resistance in breast cancer.

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“…This will decrease cell viability in BLBC cell lines. 119 It is possible that there is a different secondary signal involved in the two types of tumors, leading to contradictory tumor biological outcomes, which deserves further investigation.…”

Section: Protein Acylation In Human Diseasesmentioning

confidence: 99%

Protein acylation: mechanisms, biological functions and therapeutic targets

Shang

Liu

Hua

2022

Sig Transduct Target Ther

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Metabolic reprogramming is involved in the pathogenesis of not only cancers but also neurodegenerative diseases, cardiovascular diseases, and infectious diseases. With the progress of metabonomics and proteomics, metabolites have been found to affect protein acylations through providing acyl groups or changing the activities of acyltransferases or deacylases. Reciprocally, protein acylation is involved in key cellular processes relevant to physiology and diseases, such as protein stability, protein subcellular localization, enzyme activity, transcriptional activity, protein–protein interactions and protein–DNA interactions. Herein, we summarize the functional diversity and mechanisms of eight kinds of nonhistone protein acylations in the physiological processes and progression of several diseases. We also highlight the recent progress in the development of inhibitors for acyltransferase, deacylase, and acylation reader proteins for their potential applications in drug discovery.

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Histone Deacetylase Inhibitors (HDACi) Promote KLF5 Ubiquitination and Degradation in Basal-like Breast Cancer

Cited by 13 publications

References 61 publications

Pre-pubertal oocytes harbor altered histone modifications and chromatin configuration

Pre-pubertal oocytes harbor altered histone modifications and chromatin configuration

Upregulated PARP1 confers breast cancer resistance to CDK4/6 inhibitors via YB-1 phosphorylation

Protein acylation: mechanisms, biological functions and therapeutic targets

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