scholarly journals ThermomiR-377-3p-induced Suppression of Cirbp Expression Is Required for Effective Elimination of Cancer Cells and Cancer Stem-like Cells by Hyperthermia

2021 ◽  
Author(s):  
Tao-Yan Lin ◽  
Jun-Shuang Jia ◽  
Wei-Ren Luo ◽  
Sheng-Jun Xiao ◽  
Xiao-Lin Lin ◽  
...  
Keyword(s):  
Dna Damage ◽  
Rna Binding ◽  
Dna Damage Repair ◽  
Ectopic Expression ◽  
Killing Effect ◽  
Tumor Xenografts ◽  
Damage Repair ◽  
Tumor Killing ◽  
Therapeutic Hyperthermia

Abstract In recent years, the development of adjunctive therapeutic hyperthermia for cancer therapy has received considerable attention. However, the mechanisms underlying hyperthermia resistance are still poorly understood. In this study, we investigated the roles of cold-inducible RNA binding protein (Cirbp) in regulating hyperthermia resistance and underlying mechanisms in nasopharyngeal carcinoma (NPC). Our results firstly revealed that hyperthermia significantly attenuated the stemness property of NPC cells, while combination treatment of hyperthermia and oridonin dramatically increased the killing effect on NPC cells and cancer stem cell (CSC)-like population. Moreover, hyperthermia substantially improved the sensitivity of radiation-resistant NPC cells and CSC-like cells to radiotherapy. Hyperthermia noticeably suppressed Cirbp expression in NPC cells and xenograft tumor tissues. Furthermore, Cirbp inhibition remarkably boosted anti-tumor-killing activity of hyperthermia against NPC cells and CSC-like cells, whereas ectopic expression of Cirbp compromised tumor-killing effect of hyperthermia on these cells, indicating that Cirbp overexpression induces hyperthermia resistance. ThermomiR-377–3p improved the sensitivity of NPC cells and cancer stem-like cells to hyperthermia in vitro by directly suppressing Cirbp expression. More importantly, our results displayed the significantly boosted sensitization of tumor xenografts to hyperthermia by Cirbp silencing in vivo, but ectopic expression of Cirbp nearly completely counteracted hyperthermia-mediated tumor cell-killing effect against tumor xenografts in vivo. Mechanistically, Cirbp silencing-induced inhibition of DNA damage repair by inactivating ATM-Chk2 and ATR-Chk1 pathways, decrease in stemness and increase in cell death contributed to hyperthermic sensitization; conversely, Cirbp overexpression-induced promotion of DNA damage repair, increase in stemness and decrease in cell apoptosis contributed to hyperthermia resistance. Taken together, these findings reveal a previously unrecognized role for Cirbp in positively regulating hyperthermia resistance and suggest that thermomiR-377–3p and its target gene Cirbp represent promising targets for therapeutic hyperthermia.

scholarly journals PAICS contributes to gastric carcinogenesis and participates in DNA damage response by interacting with histone deacetylase 1/2

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Nan Huang ◽  
Chang Xu ◽  
Liang Deng ◽  
Xue Li ◽  
Zhixuan Bian ◽  
...  
Keyword(s):  
Dna Damage ◽  
Histone Deacetylase ◽  
Dna Damage Response ◽  
De Novo ◽  
Dna Damage Repair ◽  
Histone Deacetylase 1 ◽  
Damage Repair ◽  
Damage Response

AbstractPhosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), an essential enzyme involved in de novo purine biosynthesis, is connected with formation of various tumors. However, the specific biological roles and related mechanisms of PAICS in gastric cancer (GC) remain unclear. In the present study, we identified for the first time that PAICS was significantly upregulated in GC and high expression of PAICS was correlated with poor prognosis of patients with GC. In addition, knockdown of PAICS significantly induced cell apoptosis, and inhibited GC cell growth both in vitro and in vivo. Mechanistic studies first found that PAICS was engaged in DNA damage response, and knockdown of PAICS in GC cell lines induced DNA damage and impaired DNA damage repair efficiency. Further explorations revealed that PAICS interacted with histone deacetylase HDAC1 and HDAC2, and PAICS deficiency decreased the expression of DAD51 and inhibited its recruitment to DNA damage sites by impairing HDAC1/2 deacetylase activity, eventually preventing DNA damage repair. Consistently, PAICS deficiency enhanced the sensitivity of GC cells to DNA damage agent, cisplatin (CDDP), both in vitro and in vivo. Altogether, our findings demonstrate that PAICS plays an oncogenic role in GC, which act as a novel diagnosis and prognostic biomarker for patients with GC.

scholarly journals Imaging DNA Damage Repair In Vivo After 177Lu-DOTATATE Therapy

2019 ◽  
Vol 61 (5) ◽  
pp. 743-750 ◽  
Author(s):  
Edward O’Neill ◽  
Veerle Kersemans ◽  
P. Danny Allen ◽  
Samantha Y.A. Terry ◽  
Julia Baguña Torres ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Damage Repair

scholarly journals SIRT7-mediated ATM deacetylation is essential for its deactivation and DNA damage repair

2019 ◽  
Vol 5 (3) ◽  
pp. eaav1118 ◽  
Author(s):  
Ming Tang ◽  
Zhiming Li ◽  
Chaohua Zhang ◽  
Xiaopeng Lu ◽  
Bo Tu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Class Iii ◽  
Ataxia Telangiectasia Mutated ◽  
Damage Repair ◽  
Damage Response ◽  
Late Stages

The activation of ataxia-telangiectasia mutated (ATM) upon DNA damage involves a cascade of reactions, including acetylation by TIP60 and autophosphorylation. However, how ATM is progressively deactivated after completing DNA damage repair remains obscure. Here, we report that sirtuin 7 (SIRT7)–mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. In response to DNA damage, SIRT7 is mobilized onto chromatin and deacetylates ATM during the late stages of DNA damage response, when ATM is being gradually deactivated. Deacetylation of ATM by SIRT7 is prerequisite for its dephosphorylation by its phosphatase WIP1. Consequently, depletion of SIRT7 or acetylation-mimic mutation of ATM induces persistent ATM phosphorylation and activation, thus leading to impaired DNA damage repair. Together, our findings reveal a previously unidentified role of SIRT7 in regulating ATM activity and DNA damage repair.

Molecular landscape of gastric cancer (GC) harboring mutations of histone methyltransferases.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 418-418
Author(s):  
Jingyuan Wang ◽  
Joanne Xiu ◽  
Yasmine Baca ◽  
Richard M. Goldberg ◽  
Philip Agop Philip ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Progression ◽  
Dna Damage Repair ◽  
Treatment Strategies ◽  
Gene Mutations ◽  
Mutation Rates ◽  
Aberrant Expression ◽  
Damage Repair

418 Background: Alteration of histone modifications participating in transcription and genomic instability, has been recognized as an important role in tumorigenesis. Aberrant expression of histone-lysine N-methyltransferase 2 ( KMT2) family, which methylate histone H3 on lysine 4, is significantly correlated with poor survival in GC. Understanding how gene mutations of KMT2 family interact to affect cancer progression could lead to new treatment strategies. Methods: A total of 1,245 GC were analyzed using next-generation sequencing (NGS) and immunohistochemistry (IHC; Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous mutations, and MSI status was evaluated by a combination of IHC, fragment analysis and NGS. PD-L1 status was analyzed by IHC (SP142). Gene fusions were detected by Archer (N = 59) or whole-transcriptome sequencing (N = 129). Results: The overall mutation rate of genes in KMT2 family was 10.6% ( KMT2A: 1.7 %, KMT2C: 4.7%, KMT2D: 7.1%). Overall, the mutation rates were significantly higher in KMT2-mutated (MT) GC than KMT2-wild type (WT) GC, except for TP53 (43% vs 63%, p < .0001). Interestingly, among the genes with significant higher mutation rates in KMT2-MT GC, 28% (21/76) of them were related to DNA damage repair (including BRCA1/ 2, RAD50) and 33% (25/76) of them were related to chromatin remodeling (including ARID1A/ 2, SMARCA4). Overexpression of HER2, amplifications of KRAS, CDK6 and HER2 were significant lower, while PCM1 and BCL3 amplifications were significant higher in KMT2-MT, compared to KMT2-WT GC ( p < .05). Significantly higher prevalence of TMB-high ( > 17mut/MB) (49% vs 3%), MSI-H (53% vs 2%), and PD-L1 overexpression (20% vs 7%) were present in KMT2-MT GC, compared to KMT2-WT GC ( p < .001). The rates of fusions involving ARHGAP26 (19% vs 3%, p < .01)and RELA (29% vs 0%, p < .0001) were significantly higher in KMT2-MT than those in KMT2-WT GC. Conclusions: This is the largest study to investigate the distinct genomic landscape between KMT2-MT and WT GC. Our data indicates that KMT2-MT GC patients could potentially benefit from agents targeting DNA damage repair and immunotherapy, which warrants further in-vitro and in-vivo investigation.

scholarly journals Systems biology analysis of Drosophila in vivo screen data elucidates core networks for DNA damage repair in SCA1

2013 ◽  
Vol 23 (5) ◽  
pp. 1345-1364 ◽  
Author(s):  
Sam S. Barclay ◽  
Takuya Tamura ◽  
Hikaru Ito ◽  
Kyota Fujita ◽  
Kazuhiko Tagawa ◽  
...  
Keyword(s):  
Dna Damage ◽  
Systems Biology ◽  
Dna Damage Repair ◽  
Core Networks ◽  
Damage Repair ◽  
In Vivo Screen

scholarly journals VEGF knockdown enhances radiosensitivity of nasopharyngeal carcinoma by inhibiting autophagy through the activation of mTOR pathway

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Li Chen ◽  
Guoxiang Lin ◽  
Kaihua Chen ◽  
Fangzhu Wan ◽  
Renba Liang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nasopharyngeal Carcinoma ◽  
Western Blotting ◽  
Dna Damage Repair ◽  
Xenograft Model ◽  
Mtor Pathway ◽  
Angiogenic Factor ◽  
Cell Counting ◽  
Damage Repair

Abstract Vascular endothelial growth factor (VEGF) is an important pro-angiogenic factor. VEGF was reported to promote the occurrence of autophagy, which enhanced the radioresistance of tumors. The purpose of this study was to investigate the influence of VEGF silencing on the radiosensitivity of nasopharyngeal carcinoma (NPC) cells and the underlying mechanisms. The radiosensitivity of NPC cells after VEGF silencing was detected by cell counting kit 8 (CCK-8) and clonogenic assay, while cell cycle and apoptosis were detected by flow cytometry. The processes of DNA damage, repair and autophagy were examined by immunofluorescence and western blotting. The interaction between VEGF and mTOR was confirmed by western blotting and co-immunoprecipitation studies. The effect of VEGF on radiosensitivity of NPC cells was investigated in vivo using a xenograft model. Furthermore, immunohistochemistry and TUNEL assays were used to verify the relationship between autophagy and radiosensitivity in NPC after VEGF depletion. Downregulation of VEGF significantly inhibited cell proliferation and induced apoptosis of NPC cells after radiotherapy in vitro and in vivo. In addition, VEGF knockdown not only decreased autophagy level, but also delayed the DNA damage repair in NPC cells after irradiation. Mechanistically, silencing VEGF suppressed autophagy through activation of the mTOR pathway. VEGF depletion increased radiosensitivity of NPC cells by suppressing autophagy via activation of the mTOR pathway.

scholarly journals Suppression of isoprenylcysteine carboxylmethyltransferase compromises DNA damage repair

2021 ◽  
Vol 4 (12) ◽  
pp. e202101144
Author(s):  
Jingyi Tang ◽  
Patrick J Casey ◽  
Mei Wang
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Negative Impact ◽  
Parp Inhibitor ◽  
Dna Damage Repair ◽  
Mapk Signaling ◽  
Cancer Therapies ◽  
Damage Repair ◽  
Isoprenylcysteine Carboxylmethyltransferase

DNA damage is a double-edged sword for cancer cells. On the one hand, DNA damage–induced genomic instability contributes to cancer development; on the other hand, accumulating damage compromises proliferation and survival of cancer cells. Understanding the key regulators of DNA damage repair machinery would benefit the development of cancer therapies that induce DNA damage and apoptosis. In this study, we found that isoprenylcysteine carboxylmethyltransferase (ICMT), a posttranslational modification enzyme, plays an important role in DNA damage repair. We found that ICMT suppression consistently reduces the activity of MAPK signaling, which compromises the expression of key proteins in the DNA damage repair machinery. The ensuing accumulation of DNA damage leads to cell cycle arrest and apoptosis in multiple breast cancer cells. Interestingly, these observations are more pronounced in cells grown under anchorage-independent conditions or grown in vivo. Consistent with the negative impact on DNA repair, ICMT inhibition transforms the cancer cells into a “BRCA-like” state, hence sensitizing cancer cells to the treatment of PARP inhibitor and other DNA damage–inducing agents.

scholarly journals Autism-associated vigilin depletion impairs DNA damage repair

2021 ◽  
Author(s):  
Shahid Banday ◽  
Raj K. Pandita ◽  
Arjamand Mushtaq ◽  
Albino Bacolla ◽  
Ulfat Syed Mir ◽  
...  
Keyword(s):  
Dna Damage ◽  
Rna Binding ◽  
Dna Damage Repair ◽  
Strand Break ◽  
Autism Spectrum ◽  
Heterochromatin Formation ◽  
Replicative Stress ◽  
Damage Repair ◽  
Dna End Resection ◽  
Fork Stalling

Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, mRNA stability and is associated with autism-spectrum disorders and cancer, vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. Conserved from yeast to humans, vigilin is an RNA-binding protein with 14 tandemly arranged nonidentical hnRNP K type homology (KH) domains. Here we report that vigilin depletion increased cell sensitivity to cisplatin- or ionizing radiation (IR)-induced cell death and genomic instability due to defective DNA repair. Vigilin depletion delayed dephosphorylation of IR-induced γ-H2AX, elevated levels of residual 53BP1 and RIF1 foci, while reducing Rad51 and BRCA1 foci formation, DNA end resection and double strand break (DSB) repair. We show that vigilin interacts with the DNA damage response (DDR) proteins RAD51 and BRCA1, and vigilin depletion impairs their recruitment to DSB sites. Transient hydroxyurea (HU) induced replicative stress in vigilin-depleted cells increased replication fork stalling and blocked restart of DNA synthesis. Furthermore, histone acetylation promoted vigilin recruitment to DSBs preferentially in transcriptionally active genome. These findings uncover a novel vigilin role in DNA damage repair with implications for autism and cancer related disorders.

Overcoming miR-106a induced radioresistance in prostate cancer: Targeting senescence with KU-55933.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 77-77
Author(s):  
Christianne Hoey ◽  
Jessica Ray ◽  
Xiaoyong Huang ◽  
Jouhyun Jeon ◽  
Paul Christopher Boutros ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Dna Damage Repair ◽  
Clonogenic Survival ◽  
High Grade ◽  
Prostate Tumors ◽  
Normal Prostate ◽  
Damage Repair

77 Background: Prostate cancer is a leading cause of cancer related death in men worldwide, with recurrence being a major clinical problem after radiotherapy. There is an unmet need to better characterize radioresistant tumors and identify biomarkers to improve patient outcomes. Methods: We identified that miR-106a was overexpressed in radiation resistant cell lines compared to parental cells. We analyzed The Cancer Genome Atlas dataset to assess miR-106a expression in normal prostate, and low- to high-grade prostate tumors. To assess the functional role of miR-106a, we performed in vitro and in vivo assays for radiation response, including clonogenic survival, proliferation, senescence, and tumor xenograft growth after radiation. We performed gene array and pathway analyses to identify downstream effectors of miR-106a. Results: MiR-106a expression was significantly higher in prostate tumors with Gleason score > 7 compared to Gleason ≤ 7, suggesting miR-106a is involved in high grade disease. MiR-106a overexpression confers radioresistance in vitro and in vivo, by targeting LITAF. We now extend miR-106a’s effects to upregulation of ATM at the promoter level, thereby increasing ATM transcript and protein in the cell. Unexpectedly, we found that miR-106a’s mechanism of radioresistance through ATM upregulation does not alter DNA damage repair. ATM upregulation affects clonogenic survival through reduced senescence. KU-55933, a specific ATM kinase inhibitor, resensitizes miR-106a overexpressing cells to radiation by inducing senescence, a predominant mode of cell death in prostate cancer. Conclusions: Our research challenges the current paradigm of ATM and DNA damage repair by outlining another mechanism of radioresistance through alteration of senescence. Our findings suggest that miR-106a may be a promising biomarker for high-grade disease and radioresistant prostate cancer. In addition, we have identified a therapeutic intervention for miR-106a induced radioresistance. Improvements in bioavailability of KU-55933 may lead to its clinical use in combination with radiation therapy to radiosensitize miR-106a induced radioresistant prostate cancer.

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