THUMP domain containing 2 protein possibly induces resistance to cisplatin and 5‐fluorouracil in <i>in vitro</i> human esophageal squamous cell carcinoma cells as revealed by transposon activation mutagenesis

Hayashi, Masato; Kawakubo, Hirofumi; Fukuda, Kazumasa; Nakamura, Rieko; Suda, Koichi; Hayashida, Tomoko; Wada, Norihito; Kitagawa, Yuko

doi:10.1002/jgm.3135

Cited by 6 publications

(3 citation statements)

References 34 publications

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“…Here, total gene expression would predict higher expression levels, although this transcript is an NMD target that could lead to a shorter half-life. Consistent with this, decreased THUMPD2 protein expression, but not mRNA, is correlated with chemotherapy resistance (33). We further interrogated differential isoform usage between TMZsensitive and TMZ-resistant cell lines, as well as GLASS-matched patient samples, and found differential gene isoform usage that correlates with G mutations within these genes.…”

Section: Isoform Usage Changes In Tmz-resistant Cellssupporting

confidence: 64%

Temozolomide-induced guanine mutations create exploitable vulnerabilities of guanine-rich DNA and RNA regions in drug-resistant gliomas

et al. 2022

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Temozolomide (TMZ) is a chemotherapeutic agent that has been the first-line standard of care for the aggressive brain cancer glioblastoma (GBM) since 2005. Although initially beneficial, TMZ resistance is universal and second-line interventions are an unmet clinical need. Here, we took advantage of the known mechanism of action of TMZ to target guanines (G) and investigated G-rich G-quadruplex (G4) and splice site changes that occur upon TMZ resistance. We report that TMZ-resistant GBM has guanine mutations that disrupt the G-rich DNA G4s and splice sites that lead to deregulated alternative splicing. These alterations create vulnerabilities, which are selectively targeted by either the G4-stabilizing drug TMPyP4 or a novel splicing kinase inhibitor of cdc2-like kinase. Last, we show that the G4 and RNA binding protein EWSR1 aggregates in the cytoplasm in TMZ-resistant GBM cells and patient samples. Together, our findings provide insight into targetable vulnerabilities of TMZ-resistant GBM and present cytoplasmic EWSR1 as a putative biomarker.

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Section: Isoform Usage Changes In Tmz-resistant Cellssupporting

confidence: 64%

Temozolomide-induced guanine mutations create exploitable vulnerabilities of guanine-rich DNA and RNA regions in drug-resistant gliomas

et al. 2022

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“…2D). Decreased THUMPD2 protein expression is correlated with chemotherapy resistance (32). Overall, we show that TMZ-resistant cells have significant differential gene isoform usage as compared to TMZsensitive lines that correlates with gene mutation status.…”

Section: Isoform Usage Changes In Tmz-resistant Cellsmentioning

confidence: 68%

Temozolomide-induced guanine mutations create exploitable vulnerabilities of guanine-rich DNA and RNA regions in drug resistant gliomas

Tiek

Razaghi

Jin

et al. 2019

Preprint

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20Temozolomide (TMZ) is a chemotherapy agent that adds mutagenic adducts to guanine, and is first-line 21 standard of care for the aggressive brain cancer glioblastoma (GBM). Methyl guanine methyl transferase 22(MGMT) is a DNA repair enzyme that can remove O6-methyl guanine adducts prior to the development 23 of catastrophic mutations, and is associated with TMZ resistance. However, inhibition of MGMT fails 24to reverse TMZ resistance. Guanines are essential nucleotides in many DNA and RNA secondary 25 structures. In several neurodegenerative diseases (NDs), disruption of these secondary structures is 26 pathogenic. We therefore took a structural view of TMZ resistance, seeking to establish the role of 27 guanine mutations in disrupting critical nucleotide secondary structures. To test whether these have 28 functional impacts on TMZ-resistant GBM, we focused on two specific guanine-rich regions: G-29 quadruplexes (G4s) and splice sites. Here we report broad sequence-and conformation-based changes 30in G4s in acquired or intrinsic TMZ resistant vs. sensitive GBM cells, accompanied by nucleolar stress 31and enrichment of nucleolar RNA:DNA hybrids (r-loops). We further show widespread splice-altering 32 mutations, exon skipping, and deregulation of splicing-regulatory serine/arginine rich (SR) protein 33 phosphorylation in TMZ-resistant GBM cells. The G4-stabilizing ligand TMPyP4 and a novel inhibitor 34 of cdc2-like kinases (CLKs) partially normalize G4 structure and SR protein phosphorylation, 35respectively, and are preferentially growth-inhibitory in TMZ-resistant cells. Lastly, we report that the 36 G4-and RNA-binding protein EWSR1 forms aberrant cytoplasmic aggregates in response to acute TMZ 37 treatment, and these aggregates are abundant in TMZ resistant cells. Preliminary evidence suggests these 38cytoplasmic EWSR1 aggregates are also present in GBM clinical samples. This work supports altered 39 nucleotide secondary structure and splicing deregulation as pathogenic features of TMZ-resistant GBM. 40It further positions cytoplasmic aggregation of EWSR1 as a potential indicator for TMZ resistance, 41establishes the possibility of successful intervention with splicing modulatory or G4-targeting agents, 42and provides a new context in which to study aggregating RNA binding proteins. 43 et al., 2014). TMZ causes DNA damage by adding mutagenic adducts to DNA, predominantly O6-methyl 52 guanine, a lesion that can be repaired by the suicide DNA repair protein methyl guanine methyl 53 transferase (MGMT)(Tentori and Graziani, 2009). The overall survival benefit provided by TMZ is ~ 4 54 months, and rapid development of TMZ resistance occurs at least in part through demethylation of the 55 MGMT promoter, allowing for the expression of MGMT(Zhang et al., 2012). However, efforts to re-56 sensitize tumors to TMZ by inhibiting MGMT activity have been unsuccessful(Marsoner et al., 2017). 57 TMZ preferentially targets guanines(Cheung-Ong et al., 2013), critical nucleotides in many DNA 58 and RNA secondary structures(Hänsel-...

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“…The THSD7B mutation has been proven to be a cisplatin resistance factor in esophageal squamous cell carcinoma (ESCC). 22 Accordingly, THSD7B-MUT patient prognosis after platinum chemotherapy was significantly lower than that of THSD7B-WT patients ( Figure 2E and F ). The THSD7B mutation is a potential platinum resistance biomarker in SCLC.…”

Section: Discussionmentioning

confidence: 88%

THSD7B Mutation Induces Platinum Resistance in Small Cell Lung Cancer Patients

Yao¹,

Lin²,

Yi³

et al. 2022

DDDT

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Aim Several cases of small cell lung cancer (SCLC) patients demonstrate resistance to the treatment initiatives such as cisplatin after platinum chemotherapy. It is crucial to the improvement of the overall survival (OS) of SCLC patients to discover the gene mutation inducing platinum resistance within this cohort. Patients and Methods We analyzed the gene mutations significantly associated with the OS from 2 cohorts of SCLC platinum-treated patients. And then we screened out THSD7B mutation. In order to understand the mechanism between THSD7B mutation and platinum resistance, we designed gene mutation co-occurrence and mutual exclusivity analysis, gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) analysis, and Connectivity Map (CMap) analysis. Results The poor prognosis of THSD7B mutant patients may be related to the inhibition of cell death-related pathways, the up-regulation of cell invasion and metastasis pathways, and the down-regulation of immune response pathways. Lovastatin and cyclooxygenase inhibitors could be used as potential target compounds in THSD7B mutant patients, which provides reference for future research on platinum resistance. Conclusion THSD7B can be considered a reliable biomarker that effectively facilitates the prediction of poor survival in SCLC platinum-treated patients.

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THUMP domain containing 2 protein possibly induces resistance to cisplatin and 5‐fluorouracil in in vitro human esophageal squamous cell carcinoma cells as revealed by transposon activation mutagenesis

Cited by 6 publications

References 34 publications

Temozolomide-induced guanine mutations create exploitable vulnerabilities of guanine-rich DNA and RNA regions in drug-resistant gliomas

Temozolomide-induced guanine mutations create exploitable vulnerabilities of guanine-rich DNA and RNA regions in drug-resistant gliomas

Temozolomide-induced guanine mutations create exploitable vulnerabilities of guanine-rich DNA and RNA regions in drug resistant gliomas

THSD7B Mutation Induces Platinum Resistance in Small Cell Lung Cancer Patients

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