ZC3H13-mediated N6-methyladenosine modification of PHF10 is impaired by fisetin which inhibits the DNA damage response in pancreatic cancer

Huang, Chaojie; Zhou, Shuhua; Zhang, Chaolei; Jin, Yifeng; Gao, Xu; Zhou, Linhua; Ding, Guoping; Pang, Tianshu; Jia, Shengnan; Cao, Liping

doi:10.1016/j.canlet.2022.01.013

Cited by 26 publications

(15 citation statements)

References 43 publications

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“…5 ). The data on the effect of fisetin on HR is also supported by a recent report from Huang et al, who showed that HR repair efficiency in pancreatic cancer cells is diminished by fisetin treatment [ 47 ]. In this study, the authors demonstrate that fisetin inhibiting HR is due to a modification of N6-methyladenosine [ 47 ].…”

Section: Discussionsupporting

confidence: 57%

“…The data on the effect of fisetin on HR is also supported by a recent report from Huang et al, who showed that HR repair efficiency in pancreatic cancer cells is diminished by fisetin treatment [ 47 ]. In this study, the authors demonstrate that fisetin inhibiting HR is due to a modification of N6-methyladenosine [ 47 ]. However, gene ontology from our phosphoproteomic study revealed that a variety of phosphosites involved in DDR are inhibited by fisetin treatment in irradiated cells.…”

Section: Discussionsupporting

confidence: 57%

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Fisetin induces DNA double-strand break and interferes with the repair of radiation-induced damage to radiosensitize triple negative breast cancer cells

Khozooei

Lettau

Barletta

et al. 2022

J Exp Clin Cancer Res

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Background Triple-negative breast cancer (TNBC) is associated with aggressiveness and a poor prognosis. Besides surgery, radiotherapy serves as the major treatment modality for TNBC. However, response to radiotherapy is limited in many patients, most likely because of DNA damage response (DDR) signaling mediated radioresistance. Y-box binding protein-1 (YB-1) is a multifunctional protein that regulates the cancer hallmarks among them resisting to radiotherapy-induced cell death. Fisetin, is a plant flavonol of the flavonoid family of plant polyphenols that has anticancer properties, partially through inhibition of p90 ribosomal S6 kinase (RSK)-mediated YB-1 phosphorylation. The combination of fisetin with radiotherapy has not yet been investigated. Methods Activation status of the RSK signaling pathway in total cell lysate and in the subcellular fractions was analyzed by Western blotting. Standard clonogenic assay was applied to test post-irradiation cell survival. γH2AX foci assay and 3 color fluorescence in situ hybridization analyses were performed to study frequency of double-strand breaks (DSB) and chromosomal aberrations, respectively. The underlying repair pathways targeted by fisetin were studied in cells expressing genomically integrated reporter constructs for the DSB repair pathways via quantifying the expression of green fluorescence protein by flow cytometry. Flow cytometric quantification of sub-G1 cells and the protein expression of LC3-II were employed to measure apoptosis and autophagy, respectively. Kinase array and phosphoproteomics were performed to study the effect of fisetin on DDR response signaling. Results We showed that the effect of fisetin on YB-1 phosphorylation in TNBC cells is comparable to the effect of the RSK pharmacological inhibitors. Similar to ionizing radiation (IR), fisetin induces DSB. Additionally, fisetin impairs repair of IR-induced DSB through suppressing the classical non-homologous end-joining and homologous recombination repair pathways, leading to chromosomal aberration as tested by metaphase analysis. Effect of fisetin on DSB repair was partially dependent on YB-1 expression. Phosphoproteomic analysis revealed that fisetin inhibits DDR signaling, which leads to radiosensitization in TNBC cells, as shown in combination with single dose or fractionated doses irradiation. Conclusion Fisetin acts as a DSB-inducing agent and simultaneously inhibits repair of IR-induced DSB. Thus, fisetin may serve as an effective therapeutic strategy to improve TNBC radiotherapy outcome.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionsupporting

confidence: 57%

Fisetin induces DNA double-strand break and interferes with the repair of radiation-induced damage to radiosensitize triple negative breast cancer cells

Khozooei

Lettau

Barletta

et al. 2022

J Exp Clin Cancer Res

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“…In response to DSBs, ATM-mediated phosphorylation at S43 activates methyltransferase 3 (METTL3), and METTL3 modulates the accumulation of DNA-RNA hybrids at DSB sites, leading to the recruitment of RAD51 and BRCA1 for HR repair 48 . Overexpression of YTHN6-methyladenosine RNA binding protein 1 (YTHDF1), an N6-methyladenosine modification (m6A) reader, rescues the DSB DNA damage response 49 . A previous study demonstrated that TRIM44 is transcriptionally upregulated by YTHDF1 50 .…”

Section: Discussionmentioning

confidence: 99%

TRIM44 promotes BRCA1 functions in HR repair to induce Cisplatin Chemoresistance in Lung Adenocarcinoma by Deubiquitinating FLNA

Zhang¹,

Cao²,

Shi³

et al. 2022

Int. J. Biol. Sci.

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Tripartite motif-containing 44 (TRIM44) has recently been implicated in various pathological processes in numerous cancers, including lung adenocarcinoma (LUAD); however, its functional roles in chemoresistance are poorly understood. Herein, TRIM44 knockdown sensitized LUAD cells to cisplatin and enhanced cisplatin-induced apoptosis. Microarray analysis indicated that the “ Role of BRCA1 in DNA damage ” and the BRCA1 gene expression were positively regulated by TRIM44, which was further verified by immunofluorescence, qRT-PCR, and Western blotting. BRCA1 depletion effectively abolished TRIM44-modulated cisplatin resistance and regulation of homologous recombination (HR) repair. Interestingly, TRIM44 interacted with FLNA, an upstream regulator of BRCA1 as specified by STRING V 11.5, and facilitated its stability and deubiquitination. FLNA was also found to be required for the functions of TRIM44 in drug resistance. Using animal models, overexpression of TRIM44 was shown to confer resistance to cisplatin in a BRCA1- and FLNA-dependent manner. TRIM44 expression levels in tissues from cisplatin-resistant LUAD patients were significantly higher than those in tissues from cisplatin-sensitive LUAD patients. Collectively, our study results demonstrate that the TRIM44/FLNA/BRCA1 axis is involved in cisplatin chemoresistance, providing potential therapeutic targets for LUAD patients with cisplatin resistance.

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“…Toxicodendron vernicifluum (TV) or Rhus verniciflua Stokes is another traditional herbal medicine native to China, India, Japan, and Korea and is a source of flavonoids and polyphenols such as eriodictyol (ERI), fisetin (FIS) and QUE [ 37 ]. ERI and FIS share a similar backbone structure to those of API, KMF, and QUE ( Figure 1 d) and have also shown some anticancer potential in several cancer models such as breast, colon, and pancreas cancers [ 38 , 39 , 40 , 41 , 42 ]. In 2020, Li et al showed that the extract of TV (TVE) inhibited the interaction of PD-1/PD-L1 in a dose-dependent manner (IC 50 ~26 µM in a competitive ELISA— Table 1 ).…”

Section: Moleculesmentioning

confidence: 99%

Natural Blockers of PD-1/PD-L1 Interaction for the Immunotherapy of Triple-Negative Breast Cancer-Brain Metastasis

Nakhjavani

Shigdar

2022

Cancers

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The limited treatment options for triple-negative breast cancer with brain metastasis (TNBC-BM) have left the door of further drug development for these patients wide open. Although immunotherapy via monoclonal antibodies has shown some promising results in several cancers including TNBC, it cannot be considered the most effective treatment for brain metastasis. This is due to the protective role of the blood–brain barrier (BBB) which limits the entrance of most drugs, especially the bulky ones such as antibodies, to the brain. For a drug to traverse the BBB via passive diffusion, various physicochemical properties should be considered. Since natural medicine has been a key inspiration for the development of the majority of current medicines, in this paper, we review several naturally-derived molecules which have the potential for immunotherapy via blocking the interaction of programmed cell death protein-1 (PD-1) and its ligand, PD-L1. The mechanism of action, physicochemical properties and pharmacokinetics of these molecules and their theoretical potential to be used for the treatment of TNBC-BM are discussed.

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ZC3H13-mediated N6-methyladenosine modification of PHF10 is impaired by fisetin which inhibits the DNA damage response in pancreatic cancer

Cited by 26 publications

References 43 publications

Fisetin induces DNA double-strand break and interferes with the repair of radiation-induced damage to radiosensitize triple negative breast cancer cells

Fisetin induces DNA double-strand break and interferes with the repair of radiation-induced damage to radiosensitize triple negative breast cancer cells

TRIM44 promotes BRCA1 functions in HR repair to induce Cisplatin Chemoresistance in Lung Adenocarcinoma by Deubiquitinating FLNA

Natural Blockers of PD-1/PD-L1 Interaction for the Immunotherapy of Triple-Negative Breast Cancer-Brain Metastasis

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