ASPM promotes homologous recombination-mediated DNA repair by safeguarding BRCA1 stability

Xu, Shibin; Wu, Xingxuan; Wang, Peipei; Cao, Sheng‐Li; Peng, Bin; Xu, Xingzhi

doi:10.1016/j.isci.2021.102534

Cited by 23 publications

(20 citation statements)

References 56 publications

(66 reference statements)

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“…Most of these DEGs have been reported to have potential as diagnostic and prognostic biomarkers in a specific tumor or class of tumors ( Xu et al, 2019 ; Zhao et al, 2021 ; Luo et al, 2022 ), while a few have been reported to have such potential in no less than 10 tumors ( Jiang et al, 2021 ; Pan et al, 2021 ). For example, ASPM (Assembly Factor for Spindle Microtubules) facilitates the homologous recombination-mediated repair of DNA double-strand break ( Xu et al, 2021 ), is essential for mitotic spindle function during cell replication, and plays a pivotal role in the invasiveness of bladder cancer and serves as a potential prognostic biomarker for them ( Xu et al, 2019 ). The UBE2C (Ubiquitin Conjugating Enzyme E2 C) is a conjugating enzyme, that plays a crucial role in cancer progression and its upregulation has been found in various cancers, a recent study demonstrated that overexpression of UBE2C was associated with TMB, microsatellite instability, immune cell infiltration, and diverse drug sensitivities ( Jiang et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Identification of Potential Biomarkers for Pan-Cancer Diagnosis and Prognosis Through the Integration of Large-Scale Transcriptomic Data

Zhu

Xing

et al. 2022

Front. Pharmacol.

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Cancer is one of the leading causes of death worldwide, bringing a significant burden to human health and society. Accurate cancer diagnosis and biomarkers that can be used as robust therapeutic targets are of great importance as they facilitate early and effective therapies. Shared etiology among cancers suggests the existence of pan-cancer biomarkers, performance of which could benefit from the large sample size and the heterogeneity of the studied patients. In this study, we conducted a systematic RNA-seq study of 9,213 tumors and 723 para-cancerous tissue samples of 28 solid tumors from the Cancer Genome Atlas (TCGA) database, and 7,008 normal tissue samples from the Genotype-Tissue Expression (GTEx) database. By differential gene expression analysis, we identified 214 up-regulated and 186 downregulated differentially expressed genes (DEGs) in more than 80% of the studied tumors, respectively, and obtained 20 highly linked up- and downregulated hub genes from them. These markers have rarely been reported in multiple tumors simultaneously. We further constructed pan-cancer diagnostic models to classify tumors and para-cancerous tissues using 10 up-regulated hub genes with an AUC of 0.894. Survival analysis revealed that these hub genes were significantly associated with the overall survival of cancer patients. In addition, drug sensitivity predictions for these hub genes in a variety of tumors obtained several broad-spectrum anti-cancer drugs targeting pan-cancer. Furthermore, we predicted immunotherapy sensitivity for cancers based on tumor mutational burden (TMB) and the expression of immune checkpoint genes (ICGs), providing a theoretical basis for the treatment of tumors. In summary, we identified a set of biomarkers that were differentially expressed in multiple types of cancers, and these biomarkers can be potentially used for diagnosis and used as therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

Identification of Potential Biomarkers for Pan-Cancer Diagnosis and Prognosis Through the Integration of Large-Scale Transcriptomic Data

Zhu

Xing

et al. 2022

Front. Pharmacol.

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“…In different GBM cell lines and patient-derived GBM cells, ASPM knockdown by siRNA reduces proliferation, increases cell death, impairs DNA double-strand break repair, and enhances the sensitivity to X-rays [ 77 ]. ASPM knockdown increases chromosome aberrations in irradiated cells and inhibits homologous recombination [ 78 ] and non-homologous end joining (NHEJ) pathway in GBM [ 77 ]. Stable ASPM knockdown results in cell cycle arrest in G0/G1 phase [ 79 , 80 ].…”

Section: Microtubule Targeting Agents (Mtas) In Brain Tumorsmentioning

confidence: 99%

Inhibiting microcephaly genes as alternative to microtubule targeting agents to treat brain tumors

2021

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Medulloblastoma (MB) and gliomas are the most frequent high-grade brain tumors (HGBT) in children and adulthood, respectively. The general treatment for these tumors consists in surgery, followed by radiotherapy and chemotherapy. Despite the improvement in patient survival, these therapies are only partially effective, and many patients still die. In the last decades, microtubules have emerged as interesting molecular targets for HGBT, as various microtubule targeting agents (MTAs) have been developed and tested pre-clinically and clinically with encouraging results. Nevertheless, these treatments produce relevant side effects since they target microtubules in normal as well as in cancerous cells. A possible strategy to overcome this toxicity could be to target proteins that control microtubule dynamics but are required by HGBT cells much more than in normal cell types. The genes mutated in primary hereditary microcephaly (MCPH) are ubiquitously expressed in proliferating cells, but under normal conditions are selectively required during brain development, in neural progenitors. There is evidence that MB and glioma cells share molecular profiles with progenitors of cerebellar granules and of cortical radial glia cells, in which MCPH gene functions are fundamental. Moreover, several studies indicate that MCPH genes are required for HGBT expansion. Among the 25 known MCPH genes, we focus this review on KNL1, ASPM, CENPE, CITK and KIF14, which have been found to control microtubule stability during cell division. We summarize the current knowledge about the molecular basis of their interaction with microtubules. Moreover, we will discuss data that suggest these genes are promising candidates as HGBT-specific targets.

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“…S1 ). Epithelioid CD473 cells presented a higher number of variants and some of them are known to be involved in cell proliferation and DNA damage repair ( BAP1 [ 13 ], PMS2 [ 14 ], CDK12 [ 15 ], and ASPM [ 16 ]).…”

Section: Resultsmentioning

confidence: 99%

Tumor treating fields affect mesothelioma cell proliferation by exerting histotype-dependent cell cycle checkpoint activations and transcriptional modulations

et al. 2022

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Although clinical antitumor activity of Tumor Treating Fields (TTFields) has been reported in malignant pleural mesothelioma (MPM) patients, the mechanisms behind the different selectivity displayed by the various MPM histotypes to this physical therapy has not been elucidated yet. Taking advantage of the development of well characterized human MPM cell lines derived from pleural effusion and/or lavages of patients’ thoracic cavity, we investigated the biological effects of TTFields against these cells, representative of epithelioid, biphasic, and sarcomatoid histotypes. Growth inhibition and cell cycle perturbations caused by TTFields were investigated side by side with RNA-Seq analyses at different exposure times to identify pathways involved in cell response to treatment. We observed significant differences of response to TTFields among the cell lines. Cell cycle analysis revealed that the most sensitive cells (epithelioid CD473) were blocked in G2M phase followed by formation of polyploid cells. The least sensitive cells (sarcomatoid CD60) were only slightly affected by TTFields with a general delay in all cell cycle phases. Apoptosis was present in all samples, but while epithelioid cell death was already observed during the first 24 h of treatment, sarcomatoid cells needed longer times before they engaged apoptotic pathways. RNA-Seq experiments demonstrated that TTFields induced a transcriptional response already detectable at early time points (8 h). The number of differentially expressed genes was higher in CD473 than in CD60 cells, involving several pathways, such as those pertinent to cell cycle checkpoints, DNA repair, and histone modifications. Our data provide further support to the notion that the antitumor effects of TTFields are not simply related to a non-specific reaction to a physical stimulus, but are dependent on the biological background of the cells and the particular sensitivity to TTFields observed in epithelioid MPM cells is associated with a higher transcriptional activity than that observed in sarcomatoid models.

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ASPM promotes homologous recombination-mediated DNA repair by safeguarding BRCA1 stability

Cited by 23 publications

References 56 publications

Identification of Potential Biomarkers for Pan-Cancer Diagnosis and Prognosis Through the Integration of Large-Scale Transcriptomic Data

Identification of Potential Biomarkers for Pan-Cancer Diagnosis and Prognosis Through the Integration of Large-Scale Transcriptomic Data

Inhibiting microcephaly genes as alternative to microtubule targeting agents to treat brain tumors

Tumor treating fields affect mesothelioma cell proliferation by exerting histotype-dependent cell cycle checkpoint activations and transcriptional modulations

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