Chromatin Regulates Genome Targeting with Cisplatin

Zacharioudakis, Emmanouil; Agarwal, Poonam; Bartoli, Alexandra; Kunalingam, Lavaniya; Bergoglio, Valérie; Xhemalçe, Blerta; Miller, Kyle M.; Rodriguez, Raphaël

doi:10.1002/ange.201701144

Cited by 9 publications

(7 citation statements)

References 48 publications

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“…Ubiquitin ligase Speckle-type BTB-POZ protein (SPOP) limits inflammation by promoting ubiquitination of the innate signal transducer, myeloid differentiation primary response protein 88 (MYD88) [12].During mitosis induction, ubiquitin ligase CUL4-RING (CRL4s) raises the direct substrate WIPI2/ ATG18B (WD repeat domain, phosphoinositide interacting 2), an autophagy-related (ATG) protein that plays a critical role in autophagosome biogenesis through DDB1 (damage specific DNA binding protein 1), thus leading to the polyubiquitination and proteasome degradation of WIPI2 and inhibiting autophagy [13]. It has been proved that many of ubiquitin ligases are closely related to tumor development, malignant phenotype, and cisplatin resistance in cancer [14]. For example, Ubiquitin ligase HOIP [15] inhibits apoptosis induced by cisplatin.…”

Section: Introductionmentioning

confidence: 99%

Ubiquitin ligase CHAF1B induces cisplatin resistance in lung adenocarcinoma by promoting NCOR2 degradation

Gong

et al. 2020

Cancer Cell Int

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Background: Lung cancer is the most common malignant tumor in the world. The Whole-proteome microarray showed that ubiquitin ligase chromatin assembly factor 1 subunit B (CHAF1B) expression in A549/DDP cells is higher than in A549 cells. Our study explored the molecular mechanism of CHAF1B affecting cisplatin resistance in lung adenocarcinoma (LUAD). Methods: Proteome microarray quantify the differentially expressed proteins between LUAD cell line A549 and its cisplatin-resistant strain A549/DDP. Quantitative real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot (WB) confirmed the CHAF1B expression. Public databases analyzed the prognosis of LUAD patients with varied LUAD expression followed by the substrates prediction of CHAF1B. Public databases showed that nuclear receptor corepressor 2 (NCOR2) may be substrates of CHAF1B. WB detected that CHAF1B expression affected the expression of NCOR2. Cell and animal experiments and clinical data detected function and integrating mechanism of CHAF1B compounds. Results: Proteome chips results indicated that CHAF1B, PPP1R13L, and CDC20 was higher than A549 in A549/DDP. Public databases showed that high expression of CHAF1B, PPP1R13L, and CDC20 was negatively correlated with prognosis in LUAD patients. PCR and WB results indicated higher CHAF1B expression in A549/DDP cells than that in A549 cells. NCOR2 and PPP5C were confirmed to be substrates of CHAF1B. CHAF1B knockdown significantly increased the sensitivity of cisplatin in A549/DDP cells and the upregulated NCOR2 expression. CHAF1B and NCOR2 are interacting proteins and the position of interaction between CHAF1B and NCOR2 was mainly in the nucleus. CHAF1B promotes ubiquitination degradation of NCOR2. Cells and animal experiments showed that under the action of cisplatin, after knockdown of CHAF1B and NCOR2 in A549/DDP group compared with CHAF1B knockdown alone, the cell proliferation and migratory ability increased and apoptotic rate decreased, and the growth rate and size of transplanted tumor increased significantly. Immunohistochemistry suggested that Ki-67 increased, while apoptosis-related indicators caspase-3 decreased significantly. Clinical data showed that patients with high expression of CHAF1B are more susceptible to cisplatin resistance.

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Section: Introductionmentioning

confidence: 99%

Ubiquitin ligase CHAF1B induces cisplatin resistance in lung adenocarcinoma by promoting NCOR2 degradation

Gong

et al. 2020

Cancer Cell Int

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“…Drug metabolism can then be characterized by adding a fluorescent probe containing a complementary bioorthogonal functional group to the treated cells or animals. This type of "bioorthogonal chemical reporter strategy" has been used to study the metabolism of carbohydrates (24), proteins (25,26), lipids (27), nucleic acids (28)(29)(30)(31), new drug candidates (32,33) and their binding reactions in cells (34)(35)(36)(37), but no bioorthogonal reporter of prodrug anabolism has been previously reported. To evaluate this possibility, we synthesized a mimic of ara-C called "AzC" by replacing the 2′(S) hydroxyl group of ara-C with azide ( Fig.…”

mentioning

confidence: 99%

Superresolution imaging of individual replication forks reveals unexpected prodrug resistance mechanism

Triemer

Messikommer

Glasauer

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Many drugs require extensive metabolism en route to their targets. High-resolution visualization of prodrug metabolism should therefore utilize analogs containing a small modification that does not interfere with its metabolism or mode of action. In addition to serving as mechanistic probes, such analogs provide candidates for theranostics when applied in both therapeutic and diagnostic modalities. Here a traceable mimic of the widely used anticancer prodrug cytarabine (ara-C) was generated by converting a single hydroxyl group to azide, giving "AzC." This compound exhibited the same biological profile as ara-C in cell cultures and zebrafish larvae. Using azide-alkyne "click" reactions, we uncovered an apparent contradiction: drug-resistant cells incorporated relatively large quantities of AzC into their genomes and entered S-phase arrest, whereas drug-sensitive cells incorporated only small quantities of AzC. Fluorescence microscopy was used to elucidate structural features associated with drug resistance by characterizing the architectures of stalled DNA replication foci containing AzC, EdU, γH2AX, and proliferating cell nuclear antigen (PCNA). Three-color superresolution imaging revealed replication foci containing one, two, or three partially resolved replication forks. Upon removing AzC from the media, resumption of DNA synthesis and completion of the cell cycle occurred before complete removal of AzC from genomes in vitro and in vivo. These results revealed an important mechanism for the low toxicity of ara-C toward normal tissues and drug-resistant cancer cells, where its efficient incorporation into DNA gives rise to highly stable, stalled replication forks that limit further incorporation of the drug, yet allow for the resumption of DNA synthesis and cellular division following treatment.

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“…Then, they can cleave and activate the downstream effector caspases (including 3, 6, and 7), these downstream caspases can cleave the cytoskeleton and nuclear proteins (such as PARP) and induce apoptosis 34–36 . Studies have pointed out that both GEM and DDP can induce cell apoptosis 32,37–39 . After the combined use, caspase 3, 7, 9, and PARP are obviously cleaved and activated, suggesting that GEM and DDP have a synergistic effect in enhancing the apoptosis process of NPC cells.…”

Section: Discussionmentioning

confidence: 99%

“…[34][35][36] Studies have pointed out that both GEM and DDP can induce cell apoptosis. 32,[37][38][39] After the combined use, caspase 3, 7, 9, and PARP are obviously cleaved and activated, suggesting that GEM and DDP have a synergistic effect in enhancing the apoptosis process of NPC cells.…”

Section: P-gp May Be the Key Molecule That Regulates The Synergistic Effect Of Gemcitabine And Cisplatin In Npcmentioning

confidence: 99%

Gemcitabine synergizes with cisplatin to inhibit nasopharyngeal carcinoma cell proliferation and tumor growth

Zhang

Chen

et al. 2021

The FASEB Journal

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In a recently published phase III clinical trial, gemcitabine (GEM) plus cisplatin (DDP) induction chemotherapy significantly improved recurrence-free survival and overall survival and became the standard of care among patients with locoregionally advanced NPC. However, the molecular mechanisms of GEM synergized with DPP in NPC cells remain elucidated. These findings prompt us to explore the effect of the combination between GEM and DDP in NPC cell lines through proliferative phenotype, immunofluorescence, flow cytometry, and western blotting assays. In vitro studies reveal that GEM or DPP treated alone induces cell cycle arrest, promotes cell apoptosis, forces DNA damage response, and GEM synergism with DDP significantly increases the above effects in NPC cells. In vivo studies indicate that GEM or DPP treated alone significantly inhibits the tumor growth and prolongs the survival time of mice injected with SUNE1 cells compared to the control group. Moreover, the mice treated with GEM combined with DDP have smaller tumors and survive longer than those in GEM or DPP treated alone group. In addition, P-gp may be the key molecule that regulates the synergistic effect of gemcitabine and cisplatin. GEM synergizes with DPP to inhibit NPC cell proliferation and tumor growth by inducing cell cycle arrest, cell apoptosis, and DNA damage response, which reveals the mechanisms of combined GEM and DDP induction chemotherapy in improving locoregionally advanced NPC.

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Chromatin Regulates Genome Targeting with Cisplatin

Cited by 9 publications

References 48 publications

Ubiquitin ligase CHAF1B induces cisplatin resistance in lung adenocarcinoma by promoting NCOR2 degradation

Ubiquitin ligase CHAF1B induces cisplatin resistance in lung adenocarcinoma by promoting NCOR2 degradation

Superresolution imaging of individual replication forks reveals unexpected prodrug resistance mechanism

Gemcitabine synergizes with cisplatin to inhibit nasopharyngeal carcinoma cell proliferation and tumor growth

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