<scp>GRWD</scp>
            1 negatively regulates p53 via the
            <scp>RPL</scp>
            11–
            <scp>MDM</scp>
            2 pathway and promotes tumorigenesis

Kayama, Kota; Watanabe, Shinya; Takafuji, Takuya; Tsuji, Takahiro; Hironaka, Ken-ichi; Matsumoto, Masaki; Nakayama, Keiichi I.; Enari, Masato; Kohno, Takashi; Shiraishi, Kouya; Kiyono, Tohru; Yoshida, Kazumasa; Sugimoto, Nozomi; Fujita, Masatoshi

doi:10.15252/embr.201642444

Cited by 48 publications

(53 citation statements)

References 51 publications

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“…We then asked whether siRNA‐mediated silencing of MCM8 selectively hypersensitizes human fibroblasts transformed by the activated KRAS mutant G12V and the E7 of human papilloma virus type 16 (HPV16), which impairs RB, to cisplatin . As expected, transformed HFF2/T E7/KRAS cells grew rapidly compared with parental HFF2/T cells (Figure C).…”

Section: Resultsmentioning

confidence: 74%

Inhibiting the MCM8‐9 complex selectively sensitizes cancer cells to cisplatin and olaparib

et al. 2019

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MCM8 and MCM9 are paralogues of the MCM2‐7 eukaryotic DNA replication helicase proteins and play a crucial role in a homologous recombination‐mediated repair process to resolve replication stress by fork stalling. Thus, deficiency of MCM8‐9 sensitizes cells to replication stress caused, for example, by platinum compounds that induce interstrand cross‐links. It is suggested that cancer cells undergo more replication stress than normal cells due to hyperstimulation of growth. Therefore, it is possible that inhibiting MCM8‐9 selectively hypersensitizes cancer cells to platinum compounds and poly(ADP‐ribose) polymerase inhibitors, both of which hamper replication fork progression. Here, we inhibited MCM8‐9 in transformed and nontransformed cells and examined their sensitivity to cisplatin and olaparib. We found that knockout of MCM9 or knockdown of MCM8 selectively hypersensitized transformed cells to cisplatin and olaparib. In agreement with reported findings, RAS‐ and human papilloma virus type 16 E7‐mediated transformation of human fibroblasts increased replication stress, as indicated by induction of multiple DNA damage responses (including formation of Rad51 foci). Such replication stress induced by oncogenes was further increased by knockdown of MCM8, providing a rationale for cancer‐specific hypersensitization to cisplatin and olaparib. Finally, we showed that knocking out MCM9 increased the sensitivity of HCT116 xenograft tumors to cisplatin. Taken together, the data suggest that conceptual MCM8‐9 inhibitors will be powerful cancer‐specific chemosensitizers for platinum compounds and poly(ADP‐ribose) polymerase inhibitors, thereby opening new avenues to the design of novel cancer chemotherapeutic strategies.

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Section: Resultsmentioning

confidence: 74%

Inhibiting the MCM8‐9 complex selectively sensitizes cancer cells to cisplatin and olaparib

et al. 2019

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“…GRWD1 is a multifunctional protein (reviewed in (47) ), which is overexpressed in cancer cells (48) . Specifically, elevated GRWD1 expression has been shown to negatively regulate TP53 and promote tumorigenesis (49) . Since circCDYL is highly covered with GRWD1 binding sites, it could potentially function as a sponge for GRWD1 and lower its binding to targets, incl.…”

Section: Functional Studies Of Circcdyl-rbp Interactions In Hepg2mentioning

confidence: 99%

Transcriptome-wide profiles of circular RNA and RNA binding protein interactions reveal effects on circular RNA biogenesis and cancer pathway expression

Okholm

Sathe

Park

et al. 2020

Preprint

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Circular RNAs (circRNAs) are stable, often highly expressed RNA transcripts with potential to modulate other regulatory RNAs. A few circRNAs have been shown to bind RNA binding proteins (RBPs), however, little is known about the prevalence and strength of these interactions in different biological contexts. Here, we comprehensively evaluate the interplay between circRNAs and RBPs in the ENCODE cell lines, HepG2 and K562, by profiling the expression of circRNAs in fractionated total RNA-sequencing samples and analyzing binding sites of 150 RBPs in large eCLIP data sets. We show that KHSRP binding sites are enriched in flanking introns of circRNAs in both HepG2 and K562 cells, and that KHSRP depletion affects circRNA biogenesis. Additionally, we show that exons forming circRNAs are generally enriched with RBP binding sites compared to non-circularizing exons. To detect individual circRNAs with regulatory potency, we computationally identify circRNAs that are highly covered by RBP binding sites and experimentally validate circRNA-RBP interactions by RNA immunoprecipitations. We characterize circCDYL, a highly expressed circRNA with clinical and functional implications in bladder cancer, which is covered with GRWD1 binding sites. We confirm that circCDYL binds GRWD1 in vivo and functionally characterizes the effect of circCDYL-GRWD1 interactions on target genes in HepG2. Furthermore, we confirm interactions between circCDYL and RBPs in bladder cancer cells and demonstrate that circCDYL depletion affects hallmarks of cancer and perturbs the expression of key cancer genes, e.g. TP53 and MYC . Finally, we show that elevated levels of highly RBP-covered circRNAs, including circCDYL, are associated with overall survival of bladder cancer patients. Our study demonstrates transcriptome-wide and cell-type-specific circRNA-RBP interactions that could play important regulatory roles in tumorigenesis.

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“…β3 may be a direct target of transcriptional activation by p53 and involved in a proapoptotic pathway through the endoplasmic reticulum in T98G and Saos2 cell lines as described previously . Since other molecular regulation may promote ubiquitination and degradation by modulating the interaction of p53‐MDM2 , exogenous β3 may be competitively involved in the regulation of p53‐MDM2 interaction, causing p53 release and apoptosis in those cells, which do not express endogenous β3. Through this way, exogenous β3 may promote apoptosis in T98G and Saos2 cell lines.…”

Section: Discussionmentioning

confidence: 88%

Voltage‐gated sodium channels β3 subunit promotes tumorigenesis in hepatocellular carcinoma by facilitating p53 degradation

Han

Guo

et al. 2019

FEBS Letters

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The voltage‐gated sodium channels (VGSCs) are aberrantly expressed in a variety of tumors and play an important role in tumor growth and metastasis. Here, we show that VGSCs auxiliary β3 subunit, encoded by the SCN3B gene, promotes proliferation and suppresses apoptosis in HepG2 cells by promoting p53 degradation. β3 significantly increases HepG2 cell proliferation, promotes tumor growth in mouse xenograft models, and suppresses senescence and apoptosis. We found that β3 knockdown stabilizes p53 protein, leading to potentiation of p53‐induced cell cycle arrest, senescence, and apoptosis. Mechanistic studies revealed that β3 could bind to p53, promoting p53 ubiquitination and degradation by stabilizing the p53/MDM2 complex. Our results suggest that β3 is a novel negative regulator of p53 and a potential oncogenic factor.

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GRWD 1 negatively regulates p53 via the RPL 11– MDM 2 pathway and promotes tumorigenesis

Cited by 48 publications

References 51 publications

Inhibiting the MCM8‐9 complex selectively sensitizes cancer cells to cisplatin and olaparib

Inhibiting the MCM8‐9 complex selectively sensitizes cancer cells to cisplatin and olaparib

Transcriptome-wide profiles of circular RNA and RNA binding protein interactions reveal effects on circular RNA biogenesis and cancer pathway expression

Voltage‐gated sodium channels β3 subunit promotes tumorigenesis in hepatocellular carcinoma by facilitating p53 degradation

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