R2TP/PAQosome as a promising chemotherapeutic target in cancer

Kakihara, Yoshito; Kiguchi, Tetsuo; Ohazama, Atsushi; Saeki, Makio

doi:10.1016/j.jdsr.2019.08.001

Cited by 6 publications

(4 citation statements)

References 52 publications

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“…This likely reflects two independent mechanisms: a sequestration of TRBP by RPAP3, while TRBP is stabilized by HSP90, as is AGO2 (Figure 8 ). Interestingly, as already described for the R2TP complex ( 71 , 72 ), this could suggest an oncogenic function for RPAP3, which could regulate the activity of tumor suppressor miRNAs, such as Let7, in colorectal cancer ( 70 , 73 ). Indeed, downregulation of Let7 has been reported in cells of colorectal cancer patients, together with upregulation of Let7 targets such as LIN28 or HMGA2 ( 70 ), while high RPAP3 levels in tumors from patients are associated to bad prognosis ( 73 ), which is compatible with the possible regulation model we propose.…”

Section: Discussionsupporting

confidence: 61%

The interaction between RPAP3 and TRBP reveals a possible involvement of the HSP90/R2TP chaperone complex in the regulation of miRNA activity

Abel

Charron

Virciglio

et al. 2022

Nucleic Acids Research

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MicroRNAs silence mRNAs by guiding the RISC complex. RISC assembly occurs following cleavage of pre-miRNAs by Dicer, assisted by TRBP or PACT, and the transfer of miRNAs to AGO proteins. The R2TP complex is an HSP90 co-chaperone involved in the assembly of ribonucleoprotein particles. Here, we show that the R2TP component RPAP3 binds TRBP but not PACT. The RPAP3-TPR1 domain interacts with the TRBP-dsRBD3, and the 1.5 Å resolution crystal structure of this complex identifies key residues involved in the interaction. Remarkably, binding of TRBP to RPAP3 or Dicer is mutually exclusive. Additionally, we found that AGO(1/2), TRBP and Dicer are all sensitive to HSP90 inhibition, and that TRBP sensitivity is increased in the absence of RPAP3. Finally, RPAP3 seems to impede miRNA activity, raising the possibility that the R2TP chaperone might sequester TRBP to regulate the miRNA pathway.

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Section: Discussionsupporting

confidence: 61%

The interaction between RPAP3 and TRBP reveals a possible involvement of the HSP90/R2TP chaperone complex in the regulation of miRNA activity

Abel

Charron

Virciglio

et al. 2022

Nucleic Acids Research

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“…PIH1D1 is a component of R2TP complex and also known tobe unstable protein which is stabilized by Tah1 (RPAP3) (RPAP3 SPLICING). R2TP signi cantly expresses higher in cancer cells and also stabilizes the expression of mTOR which contributes in cancer malignancy [13].…”

Section: Discussionmentioning

confidence: 99%

“…Breast and pancreatic tumours exhibit considerable overexpression of ECD, and these overexpressions are directly correlated with unfavourable prognostic indicators and poor patient survival [11]. PIH1-C is a CS domain, a motif found in several HSP90/Hsp82 co-chaperones, and is required for Tah1 and RPAP3 binding [12]. Despite the intensive study of PIH1D1 in many cancers, there is limited research regarding PIH1D1 in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

PIH1D1 as a potential biomarkers candidate for diagnostic approach in Breast Cancer

Singh,

jit,

Verma

et al. 2023

Preprint

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The R2TP complex is a co-chaperone conserved from Yeast to mammals and comprises of RUVBL1, RUVBL2, PIH1D1 and RPAP3 in Human is known to be a specialized Co-chaperone of Hsp-90 protein. A number of multi-subunit complexes, such as RNA polymerase II, tiny nucleolar ribonucleoproteins, and complexes containing phosphatidylinositol-3-kinase-like kinases, are assembled and matured by this protein complex. The expression level of PIH1D1 were analyzed across cancers using TIMER 2 and compared normal and breast cancer tissues using TNM plot. Survival Plot were done by GEPIA. TCGA data analyzed for the evaluation of the expression of PIH1D1 in breast cancer and both Histological and Clusters and Interaction analysis with the help of Human Protein atlas Database. The results indicate that PIH1D1 is highly expressed in breast cancer than normal tissues. So, PIH1D1 can be used for early detection as well as indicators of prognosis of Breast. Moreover, PIH1D1 may become the target of immunotherapy for Breast cancer in the future. Our current study is limited, though, because the data we examined came exclusively from bioinformatics source. Through both in vivo and in vitro investigations, we will investigate the possible mechanism of PIH1D1 in breast cancer cell lines and clinical tissues.

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“…The variant rs3738952 was screened in Chinese lung carcinoma patients, but it remained unclear whether it could result in any dysfunctions [ 43 ]. PIH1D1 may impact the oncogenesis and treatment reaction [ 44 ]. It could interact with the MTOR complex and is overexpressed in breast cancer [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Discriminating Potential Genetic Markers for Complete Response and Non-Complete Response Patients to Neoadjuvant Chemotherapy with Locally Advanced Rectal Cancer

Bagaria

Kim

Bagyinszky

et al. 2022

IJERPH

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Background: Neoadjuvant chemoradiotherapy (nCRT) prior to surgery is considered standard therapy for locally advanced rectal cancer. Unfortunately, most patients with rectal cancer are resistant to radiotherapy. This might be a genetic cause. The role of certain rectal cancer-causing genes has not been completely elucidated. This study aims to investigate the genes responsible for locally advanced rectal cancer patients not reacting to radiotherapy. Methods: Whole exome sequencing of the DNA samples was performed on the samples. Bioinformatic analysis on the subjects was established. Individual genetic information was screened to identify differently expressed genes that more frequently appeared in non-complete response (NCR) compared to complete response (CR) patients after nCRT. All variations were verified by Sanger sequencing. Results: Genotyping information and pathway analyses of the samples indicated genes such as FLCN, CALML5, and ANTXR1 to be commonly mutated in CR group, whereas genes such as GALNTL14, CNKSR1, ACD, and CUL3 were more commonly mutated in the NCR group. Chi-square test revealed some significant variants (<0.05) such as rs3744124 (FLCN), rs28365986 (ANTXR1), rs10904516 (CALML5), rs3738952 (CUL3), rs13394 and rs2293013 (PIH1D1), rs2274531 (GPA33), rs4963048 (BRSK2), rs17883366 (IL3RA), rs2297575 (PSMD5), rs2288101 (GALNT14), and rs11954652 (DCTN4). Conclusion: Identifying an array of genes that separate NCRs from CRs would lead to finding genetic biomarkers for early detection of rectal cancer patients that are resistant to nCRT. A further investigation to validate the significance of genetic biomarkers to segregate NCRs from CRs should be performed with a larger CRC dataset. Protein expression levels, as well as transcriptomic analysis, would also help us understand the mechanism of how these genes could play a role in preventing radiation therapy to patients. This would be essential to prevent redundant radiation therapy.

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R2TP/PAQosome as a promising chemotherapeutic target in cancer

Cited by 6 publications

References 52 publications

The interaction between RPAP3 and TRBP reveals a possible involvement of the HSP90/R2TP chaperone complex in the regulation of miRNA activity

The interaction between RPAP3 and TRBP reveals a possible involvement of the HSP90/R2TP chaperone complex in the regulation of miRNA activity

PIH1D1 as a potential biomarkers candidate for diagnostic approach in Breast Cancer

Discriminating Potential Genetic Markers for Complete Response and Non-Complete Response Patients to Neoadjuvant Chemotherapy with Locally Advanced Rectal Cancer

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