HSP110 translocates to the nucleus upon genotoxic chemotherapy and promotes DNA repair in colorectal cancer cells

Causse, Sébastien; Marcion, Guillaume; Chanteloup, Gaëtan; Uyanik, Burhan; Boudesco, Christophe; Grigorash, Bogdan B.; Douhard, Romain; Dias, A.; Dumetier, Baptiste; Dondaine, Lucile; Gozzi, Gustavo Jabor; Moussay, Etienne; Paggetti, Jérôme; Mirjolet, Céline; Thonel, Aurélie de; Dubrez, Laurence; Demidov, Oleg N.; Gobbo, Jessica; Garrido, Carmen

doi:10.1038/s41388-018-0616-2

Cited by 29 publications

(25 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, two categories of proteins with one member previously associated with MSI were downregulated in MSI cells. The heat shock proteins HSPA4L, DNAJB14, and HSPH1 (also known as HSP110) were also downregulated in MSI, the latter of which has an established role in MSI disease (Causse et al, 2019;Dorard et al, 2011). The histone methyltransferase (HMT) proteins KMT2B, KMT2D, and SETD1B were also downregulated in MSI cells; SETD1B was previously associated with MSI colorectal and gastric cancer (Choi et al, 2014).…”

Section: Multiple Protein Complexes Are Differentially Expressed In Microsatellite Instable Cell Linesmentioning

confidence: 99%

Quantitative Proteomics of the Cancer Cell Line Encyclopedia

Nusinow

Szpyt

Ghandi

et al. 2020

Cell

705

649

View full text Add to dashboard Cite

show abstract

Section: Multiple Protein Complexes Are Differentially Expressed In Microsatellite Instable Cell Linesmentioning

confidence: 99%

Quantitative Proteomics of the Cancer Cell Line Encyclopedia

Nusinow

Szpyt

Ghandi

et al. 2020

Cell

705

649

View full text Add to dashboard Cite

show abstract

“…The implication of this chaperone in different cellular functions may explain its tumorigenic effect. First, HSP110 is a powerful chaperone with antiaggregation properties that is involved in double‐stand break DNA repair 33 . Second, HSP110 has been shown to inhibit apoptosis, although how it happens at a molecular level remains elusive.…”

Section: Discussionmentioning

confidence: 99%

Nanofitins targeting heat shock protein 110: An innovative immunotherapeutic modality in cancer

Marcion

Hermetet

Neiers

et al. 2021

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

The presence of an inactivating heat shock protein 110 (HSP110) mutation in colorectal cancers has been correlated with an excellent prognosis and with the ability of HSP110 to favor the formation of tolerogenic (M2-like) macrophages. These clinical and experimental results suggest a potentially powerful new strategy against colorectal cancer: the inhibition of HSP110. In this work, as an alternative to neutralizing antibodies, Nanofitins (scaffold~7 kDa proteins) targeting HSP110 were isolated from the screening of a synthetic Nanofitin library, and their capacity to bind (immunoprecipitation, biolayer interferometry) and to inhibit HSP110 was analyzed in vitro and in vivo. Three Nanofitins were found to inhibit HSP110 chaperone activity. Interestingly, they share a high degree of homology in their variable domain and target the peptide-binding domain of HSP110. In vitro, they inhibited the ability of HSP110 to favor M2-like macrophages. The Nanofitin with the highest affinity, A-C2, was studied in the CT26 colorectal cancer mice model. Our PET/scan experiments demonstrate that A-C2 may be localized within the tumor area, in accordance with the reported HSP110 abundance in the tumor microenvironment. A-C2 treatment reduced tumor growth and was associated with an increase in immune cells infiltrating the tumor and particularly cytotoxic macrophages. These results were confirmed in a chicken chorioallantoic membrane tumor model. Finally, we showed the complementarity between A-C2 and an anti-PD-L1 strategy in the in vivo and in ovo tumor models. Overall, Nanofitins appear to be promising new immunotherapeutic lead compounds.

show abstract

“…In addition, high transcript level of HSPD1 was associated with the resistance to hormonal therapy, and a short 4-gene signature including HSPD1 might effectively predict tamoxifenresistance (Sotgia, Fiorillo & Lisanti, 2017). The function of HSPH1 in DNA repair may partially explain the higher resistance to genotoxic drugs of colorectal cancers expressing higher levels of HSPH1 (Causse et al, 2018). ATIC was associated with resistance to methotrexate (You et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of critical genes associated with tamoxifen resistance in breast cancer

Zhang

Jiang

Hong

et al. 2020

PeerJ

View full text Add to dashboard Cite

Background Tamoxifen resistance in breast cancer is an unsolved problem in clinical practice. The aim of this study was to determine the potential mechanisms of tamoxifen resistance through bioinformatics analysis. Methods Gene expression profiles of tamoxifen-resistant MCF-7/TR and MCF-7 cells were acquired from the Gene Expression Omnibus dataset GSE26459, and differentially expressed genes (DEGs) were detected with R software. We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses using Database for Annotation, Visualization and Integrated Discovery. A protein–protein interaction (PPI) network was generated, and we analyzed hub genes in the network with the Search Tool for the Retrieval of Interacting Genes database. Finally, we used siRNAs to silence the target genes and conducted the MTS assay. Results We identified 865 DEGs, 399 of which were upregulated. GO analysis indicated that most genes are related to telomere organization, extracellular exosomes, and binding-related items for protein heterodimerization. PPI network construction revealed that the top 10 hub genes—ACLY, HSPD1, PFAS, GART, TXN, HSPH1, HSPE1, IRAS, TRAP1, and ATIC—might be associated with tamoxifen resistance. Consistently, RT-qPCR analysis indicated that the expression of these 10 genes was increased in MCF-7/TR cells comparing with MCF-7 cells. Four hub genes (TXN, HSPD1, HSPH1 and ATIC) were related to overall survival in patients who accepted tamoxifen. In addition, knockdown of HSPH1 by siRNA may lead to reduced growth of MCF-7/TR cell with a trend close to significance (P = 0.07), indicating that upregulation of HSPH1 may play a role in tamoxifen resistance. Conclusion This study revealed a number of critical hub genes that might serve as therapeutic targets in breast cancer resistant to tamoxifen and provided potential directions for uncovering the mechanisms of tamoxifen resistance.

show abstract

HSP110 translocates to the nucleus upon genotoxic chemotherapy and promotes DNA repair in colorectal cancer cells

Cited by 29 publications

References 20 publications

Quantitative Proteomics of the Cancer Cell Line Encyclopedia

Quantitative Proteomics of the Cancer Cell Line Encyclopedia

Nanofitins targeting heat shock protein 110: An innovative immunotherapeutic modality in cancer

Identification and characterization of critical genes associated with tamoxifen resistance in breast cancer

Contact Info

Product

Resources

About