New primers for sex identification in the Chukar partridges (Alectoris chukar).

1. Male and female Chukar partridges are difficult to differentiate based on their morphology or by the Chromobox-Helicase-DNA binding (CHD) during early growth.2. The current study developed a novel, simple, low-cost and rapid sexing protocol for Chukar partridges based on the newly defined sexing gene ubiquitin-associated protein 2 (UBAP2).3. The length of polymorphism between UBAP2-W and UBAP2-Z homologous genes allows for easy sex discrimination in this species. Molecular sexing analysis was based on the simultaneous amplification of both genes, resulting in two distinct amplicons (947 bp and 535 bp) in heterogametic females and only a single band (535 bp) in homogametic males, which is easy to detect with agarose gel electrophoresis.4. This technique is simple and convenient for genetic sex determination in Chukar partridges.

The Role of Heat-Induced Stress Granules in the Blood-Testis Barrier of Mice.

Stress granules (SGs) are membraneless ribonucleoprotein (RNP)-based cellular foci formed in response to stress, facilitating cell survival by protecting against damage. Mammalian spermatogenesis should be maintained below body temperature for proper development, indicating its vulnerability to heat stress (HS). In this study, biotin tracer permeability assays showed that the inhibition of heat-induced SG assembly in the testis by 4-8 mg/kg cycloheximide significantly increased the percentage of seminiferous tubules with a damaged blood-testis barrier (BTB). Western blot results additionally revealed that the suppression of heat-induced SG assembly in Sertoli cell line, TM4 cells, by RNA inference of G3bp1/2 aggravated the decline in the BTB-related proteins ZO-1, ß-Catenin and Claudin-11, indicating that SGs could protect the BTB against damage caused by HS. The protein components that associate with SGs in Sertoli cells were isolated by sequential centrifugation and immunoprecipitation, and were identified by liquid chromatography with tandem mass spectrometry. Gene Ontology and KEGG pathway enrichment analysis revealed that their corresponding genes were mainly involved in pathways related to proteasomes, nucleotide excision repair, mismatch repair, and DNA replication. Furthermore, a new SG component, the ubiquitin associated protein 2 (UBAP2), was found to translocate to SGs upon HS in TM4 cells by immunofluorescence. Moreover, SG assembly was significantly diminished after UBAP2 knockdown by RNA inference during HS, suggesting the important role of UBAP2 in SG assembly. In addition, UBAP2 knockdown reduced the expression of ZO-1, ß-Catenin and Claudin-11, which implied its potential role in the function of the BTB. Overall, our study demonstrated the role of SGs in maintaining BTB functions during HS and identified a new component implicated in SG formation in Sertoli cells. These findings not only offer novel insights into the biological functions of SGs and the molecular mechanism of low fertility in males in summer, but also potentially provide an experimental basis for male fertility therapies.

The NSP3 protein of SARS-CoV-2 binds fragile X mental retardation proteins to disrupt UBAP2L interactions.

Viruses interact with numerous host factors to facilitate viral replication and to dampen antiviral defense mechanisms. We currently have a limited mechanistic understanding of how SARS-CoV-2 binds host factors and the functional role of these interactions. Here, we uncover a novel interaction between the viral NSP3 protein and the fragile X mental retardation proteins (FMRPs: FMR1, FXR1-2). SARS-CoV-2 NSP3 mutant viruses preventing FMRP binding have attenuated replication in vitro and reduced levels of viral antigen in lungs during the early stages of infection. We show that a unique peptide motif in NSP3 binds directly to the two central KH domains of FMRPs and that this interaction is disrupted by the I304N mutation found in a patient with fragile X syndrome. NSP3 binding to FMRPs disrupts their interaction with the stress granule component UBAP2L through direct competition with a peptide motif in UBAP2L to prevent FMRP incorporation into stress granules. Collectively, our results provide novel insight into how SARS-CoV-2 hijacks host cell proteins and provides molecular insight into the possible underlying molecular defects in fragile X syndrome.

Circ_UBAP2 exacerbates proliferation and metastasis of OS via targeting miR-665/miR-370-3p/HMGA1 axis.

Circ_UBAP2 is extensively engaged in regulating the development of various malignancies, containing osteosarcoma (OS). However, its biological significance and function are not fully understood. In this study, we found that circ_UBAP2 and HMGA1 levels were up-regulated, and miR-370-3p and miR-665 expressions were decreased in osteosarcoma tissues. Inhibition of circ_UBAP2 or HMGA1 expression in OS cells, cell viability, invasion and migration abilitities were notably hindered, and cell apoptosis abilities were increased. Bioinformatics analysis predicted that miR-665 and miR-370-3p were the downstream targets of circ_UBAP2, and the dual luciferase experiment demonstrated the correlation between them. In addition, inhibition of miR-665 and miR-370-3p expression could significantly reverse the impact of knocking down circ_UBAP2 on OS cells. HMGA1 was discovered to become the downstream target of both miR-665 and miR-370-3p. It was shown that over-expression of miR-665 or miR-370-3p notably stimulated the cell growth, invasion, and migration of osteosarcoma cells, while hindered cell apoptosis. Nevertheless, this effect could be reversed by concurrent over-expression of HMGA1. Our data strongly prove that circ_UBAP2 makes a vital impact on promoting the proliferation, invasion as well as migration of osteosarcoma cells via down-regulating the level of miR-665 and miR-370-3p, and later up-regulating the level of HMGA1. In conclusion, circ_UBAP2 is upregulated in osteosarcoma, and it competitively adsorbs miR-370-3p and miR-665, resulting in up-regulation of HMGA1, thus promoting OS development.

Pancreatic Ubap2 deletion regulates glucose tolerance, inflammation, and protection from cerulein-induced pancreatitis.

Ubiquitin-binding associated protein 2 (UBAP2) is reported to promote macropinocytosis and pancreatic adenocarcinoma (PDAC) growth, however, its role in normal pancreatic function remains unknown. We addressed this knowledge gap by generating UBAP2 knockout (U2KO) mice under a pancreas-specific Cre recombinase (Pdx1-Cre). Pancreatic architecture remained intact in U2KO animals, but they demonstrated slight glucose intolerance compared to controls. Upon cerulein challenge to induce pancreatitis, U2KO animals had reduced levels of several pancreatitis-relevant cytokines, amylase and lipase in the serum, reduced tissue damage, and lessened neutrophil infiltration into the pancreatic tissue. Mechanistically, cerulein-challenged U2KO animals revealed reduced NF-κB activation compared to controls. In vitro promoter binding studies confirmed the reduction of NF-κB binding to its target molecules supporting UBAP2 as a new regulator of inflammation in pancreatitis and may be exploited as a therapeutic target in future to inhibit pancreatitis.

PCK1 activates oncogenic autophagy via down-regulation Serine phosphorylation of UBAP2L and antagonizes colorectal cancer growth.

Phosphoenolpyruvate carboxykinase 1 (PCK1) is the rate-limiting enzyme in gluconeogenesis. PCK1 is considered an anti-oncogene in several human cancers. In this study, we aimed to determine the functions of PCK1 in colorectal cancer (CRC). PCK1 expression in CRC tissues was tested by western blot and immunohistochemistry analyses and associations of PCK1 level with clinicopathological characteristics and disease survival evaluated. Further, we studied the effect of PCK1 on CRC cell proliferation and the underlying mechanisms. Our results show that PCK1 is expressed at significantly lower levels in CRC than in control tissues. High PCK1 expression was correlated with smaller tumor diameter and less bowel wall invasion (T stage). Overexpression and knockdown experiments demonstrated that PCK1 inhibits CRC cell growth both in vitro and in vivo. Mechanistically, PCK1 antagonizes CRC growth via inactivating UBAP2L phosphorylation at serine 454 and enhancing autophagy. Overall, our findings reveal a novel molecular mechanism involving PCK1 and autophagy, and highlight PCK1 as a promising candidate therapeutic target in CRC.

UBAP2L-dependent coupling of PLK1 localization and stability during mitosis.

PLK1 is an important regulator of mitosis whose protein levels and activity fluctuate during the cell cycle. PLK1 dynamically localizes to various mitotic structures to regulate chromosome segregation. However, the signaling pathways linking localized PLK1 activity to its protein stability remain elusive. Here, we identify the Ubiquitin-Binding Protein 2-Like (UBAP2L) that controls both the localization and the protein stability of PLK1. We demonstrate that UBAP2L is a spindle-associated protein whose depletion leads to severe mitotic defects. UBAP2L-depleted cells are characterized by increased PLK1 protein levels and abnormal PLK1 accumulation in several mitotic structures such as kinetochores, centrosomes and mitotic spindle. UBAP2L-deficient cells exit mitosis and enter the next interphase in the presence of aberrant PLK1 kinase activity. The C-terminal domain of UBAP2L mediates its function on PLK1 independently of its role in stress response signaling. Importantly, the mitotic defects of UBAP2L-depleted cells are largely rescued by chemical inhibition of PLK1. Overall, our data suggest that UBAP2L is required to fine-tune the ubiquitin-mediated PLK1 turnover during mitosis as a means to maintain genome fidelity.

Ubiquitin Binding Protein 2-Like (UBAP2L): is it so NICE After All?

Ubiquitin Binding Protein 2-like (UBAP2L, also known as NICE-4) is a ubiquitin- and RNA-binding protein, highly conserved in metazoans. Despite its abundance, its functions have only recently started to be characterized. Several studies have demonstrated the crucial involvement of UBAP2L in various cellular processes such as cell cycle regulation, stem cell activity and stress-response signaling. In addition, UBAP2L has recently emerged as a master regulator of growth and proliferation in several human cancers, where it is suggested to display oncogenic properties. Given that this versatile protein is involved in the regulation of multiple and distinct cellular pathways, actively contributing to the maintenance of cell homeostasis and survival, UBAP2L might represent a good candidate for future therapeutic studies. In this review, we discuss the current knowledge and latest advances on elucidating UBAP2L cellular functions, with an aim to highlight the importance of targeting UBAP2L for future therapies.

UBAP2/UBAP2L regulate UV-induced ubiquitylation of RNA polymerase II and are the human orthologues of yeast Def1.

During transcription, RNA polymerase II (RNAPII) faces numerous obstacles, including DNA damage, which can lead to stalling or arrest. One mechanism to contend with this situation is ubiquitylation and degradation of the largest RNAPII subunit, RPB1 - the 'last resort' pathway. This conserved, multi-step pathway was first identified in yeast, and the functional human orthologues of all but one protein, RNAPII Degradation Factor 1 (Def1), have been discovered. Here we show that following UV-irradiation, human Ubiquitin-associated protein 2 (UBAP2) or its paralogue UBAP2-like (UBAP2L) are involved in the ubiquitylation and degradation of RNAPII through the recruitment of Elongin-Cul5 ubiquitin ligase. Together, our data indicate that UBAP2 and UBAP2L are the human orthologues of yeast Def1, and so identify the key missing proteins in the human last resort pathway.

Circular RNA circ_UBAP2 facilitates the progression of osteosarcoma by regulating microRNA miR-637/high-mobility group box (HMGB) 2 axis.

Circular RNA circ_UBAP2 has been reported to be closely associated with various tumors. The present work focused on exploring the roles of circ_UBAP2 and its molecular mechanism in osteosarcoma (OS). Circ_UBAP2, miR-637, and high-mobility group box (HMGB) 2 levels in OS cells and tissues were detected by quantitative real-time polymerase chain reaction. The relationship between miR-637 and circ_UBAP2, as well as between miR-637 and HMGB2, was predicted and examined through bioinformatics analysis and luciferase reporter gene experiments. Moreover, OS cell growth, invasion, migration, and apoptosis were detected using the cell counting kit-8 (CCK-8), Transwell and flow cytometry assays, respectively. HMGB2 protein levels were measured using Western blotting. Xenograft tumor formation assay was also performed. Circ_UBAP2 showed high expression levels in OS tissues and cells, which was directly proportional to metastasis and clinical stage of OS. The overexpression of circ_UBAP2 enhanced the growth, invasion, and migration of OS cells, but suppressed their apoptosis. In contrast, circ_UBAP2 silencing had opposite effects. Furthermore, miR-637 served as a downstream target of circ_UBAP2, which played opposite roles to circ_UBAP2 in OS. More importantly, HMGB2 served as miR-637's downstream target. The xenograft experiments in nude mice also proved that knockdown of circ_UBAP2 could increase miR-637 expression, but decrease HMGB2 expression, thus alleviating OS progression. Mechanistically, circ_UBAP2 exerts a cancer-promoting effect on OS by downregulating miR-637 and upregulating the expression of HMGB2. Circ_UBAP2 plays a promoting role in OS, and the circ_UBAP2/miR-637/HMGB2 axis is involved in OS progression.

Ubiquitin-associated protein 2 like (UBAP2L) enhances growth and metastasis of gastric cancer cells.

Ubiquitin-proteasome pathway has emerged as therapeutic targets for cancer. GEPIA database analysis showed that the expression of ubiquitin-associated protein 2 like (UBAP2L) in gastric cancer specimens was significantly higher than that in non-tumor tissue, and its high expression is associated with poor survival of gastric cancer patients. This study aims to investigate the role of UBAP2L in gastric cancer. Real-time PCR and western blot results showed that UBAP2L expression was upregulated in gastric cancer cell lines. Loss- and gain-of-function experiments demonstrated that silencing of UBAP2L inhibited proliferation, migration and invasion, and induced apoptosis of gastric cancer cells, and overexpression of UBAP2L played opposite roles. Nude mice inoculated with UBAP2L-silenced gastric cancer cells generated smaller xenografted tumors in vivo. Furthermore, UBAP2L activated Wnt/ß-catenin signaling - the accumulation of nuclear ß-catenin and the expression of its downstream targets (cyclin D1, AXIN-2 and c-MYC) was facilitated, whereas knockdown of UBAP2L deactivated this signaling. The tumor-suppressing effect of UBAP2L silencing was abolished by forced activation of ß-cateninS33A. UBAP2L has been confirmed as a novel and direct target of miR-148b-3p. The anti-tumor effect of miR-148b-3p was partly reversed by UBAP2L overexpression. The expression of miR-148b-3p was negatively correlated with that of UBAP2L in gastric cancer samples. Overall, our study indicates that UBAP2L is required to maintain malignant behavior of gastric cancer cells, which involves the activation of Wnt/ß-catenin signaling pathway. We propose UBAP2L as a potential therapeutic target against gastric cancer.

Downregulation of circ-UBAP2 ameliorates oxidative stress and dysfunctions of human retinal microvascular endothelial cells (hRMECs) via miR-589-5p/EGR1 axis.

Hsa_circ_0001850_circ_0001850 (circ-UBAP2) is reported to be upregulated in diabetic retinopathy (DR). However, its role in high glucose (HG)-triggered oxidative stress and vascular dysfunction in DR is unclear. This study aimed to investigate the potential of circUBAP2 in DR. The content of malondialdehyde (MDA), and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) were analyzed using the corresponding kits. Western blotting was performed to detect the protein expression of Nrf2, HO-1, and SOD-1. MTT assay was conducted to assess cell viability. A transwell migration assay was used to determine the migration ability of human retinal microvascular endothelial cells (hRMECs). A Matrigel tube formation assay was performed to analyze tube formation. The targeting relationships were verified using a luciferase reporter assay. We found that the circ-UBAP2 expression increased in DR patients and HG-treated hRMECs. Downregulation of circ-UBAP2 ameliorated HG-induced oxidative stress and dysfunction of hRMECs. Mechanistically, circ-UBAP2 sponges miR-589-5p, which is downregulated under hyperglycemic conditions. In addition, EGR1 was confirmed to be a target gene of miR-589-5p and was overexpressed in HG-treated hRMECs. In addition, EGR1 reversed the effects of miR-589-5p and induced oxidative stress and dysfunction in hRMECs. Taken together, knockdown of circ-UBAP2 relieved HG-induced oxidative stress and dysfunctions of the hRMECs through the miR-589-5p/EGR1 axis, which may offer a promising therapeutic target for DR.

PQN-59 and GTBP-1 contribute to stress granule formation but are not essential for their assembly in C. elegans embryos.

When exposed to stressful conditions, eukaryotic cells respond by inducing the formation of cytoplasmic ribonucleoprotein complexes called stress granules. Here, we use C. elegans to study two proteins that are important for stress granule assembly in human cells - PQN-59, the human UBAP2L ortholog, and GTBP-1, the human G3BP1 and G3BP2 ortholog. Both proteins assemble into stress granules in the embryo and in the germline when C. elegans is exposed to stressful conditions. Neither of the two proteins is essential for the assembly of stress-induced granules, as shown by the single and combined depletions by RNAi, and neither pqn-59 nor gtbp-1 mutant embryos show higher sensitivity to stress than control embryos. We find that pqn-59 mutants display reduced progeny and a high percentage of embryonic lethality, phenotypes that are not dependent on stress exposure and that are not shared with gtbp-1 mutants. Our data indicate that, in contrast to human cells, PQN-59 and GTBP-1 are not required for stress granule formation but that PQN-59 is important for C. elegans development.

Circular RNA UBAP2 promotes the proliferation of prostate cancer cells via the miR-1244/MAP3K2 axis.

Prostate cancer (PCa) is a common male malignant disease with a high incidence, which can seriously affect the quality of life of patients. The survival rate of patients with PCa has improved to 98.6%; however, new insights for the molecular mechanism are still urgently required. Circular RNA (circ)UBAP2 is a tumor-associated circRNA that has been demonstrated to promote the progression of various types of cancer. CircUBAP2 has been demonstrated to be significantly upregulated in PCa, but its role in the progression of PCa remains unclear. The present study aimed to provide an improved understanding of the regulatory mechanism of circUBAP2 in PCa. circUBAP2 expression was identified to be upregulated in four PCa cell lines and clinical tissues by using reverse transcription-quantitative PCR analysis. Binding sites analysis and luciferase reporter gene assay indicated that the microRNA(miR)-1244/MAP3K2 axis was the target of circUBAP2. Gain-of-function assays revealed that circUBAP2 promoted the proliferation of PCa cells by sponging miR-1244 and promoting the MAP3K2 axis. The present findings may be essential for providing new strategies in the diagnosis and targeted therapy of PCa.

Norcantharidin-blocked ANXA2P2 inhibits fibroblast proliferation by increasing UBAP2L mRNA stability through LIN28B.

AIMS: Norcantharidin (NCTD) exhibits antitumor, anti-inflammatory, and anti-fibrosis properties, which makes NCTD an attractive candidate for the treatment of pathological scars. This study was designed to investigate the potential effects of NCTD on fibroblast proliferation and explore the underlying mechanisms. MATERIALS AND METHODS: First, cell viability and cell apoptosis were evaluated to determine the effects of NCTD on human skin fibroblasts, at 10, 50, and 100 µM. To explore the mechanism, bioinformatics analyses, chromatin immunoprecipitation, RNA immunoprecipitation, and RNA pulldown assays, and luciferase reporter assays were performed to verify the relationships among NCTD, signal transducer and activator of transcription 3 (STAT3), annexin A2 pseudogene 2 (ANXA2P2), and ubiquitin-associated protein 2-like (UBAP2L) mRNA in fibroblasts. Loss-of-function experiments were performed to investigate the roles played by STAT3, ANXA2P2, and UBAP2L in the proliferation and apoptosis of fibroblasts. KEY FINDINGS: We found that NCTD administration induced fibroblast apoptosis and inhibited fibroblast proliferation in a dose-dependent manner. Mechanistically, NCTD inhibited ANXA2P2 transcription through the inhibition of STAT3 phosphorylation. Subsequently, ANXA2P2 was found to enhance the physical interaction between UBAP2L mRNA and lin-28 homolog B (LIN28B), which increased the stability and levels of UBAP2L mRNA. Loss-of-function assays demonstrated that ANXA2P2 and UBAP2L knockdown induced fibroblast apoptosis and suppressed fibroblast proliferation. SIGNIFICANCE: In conclusion, we confirmed that NCTD inhibits fibroblast proliferation by inhibiting the STAT3/ANXA2P2/UBAP2L axis, which suggested that NCTD could represent a new candidate for the treatment of pathological scars.

Circ-UBAP2 functions as sponges of miR-1205 and miR-382 to promote glioma progression by modulating STC1 expression.

BACKGROUND: Circular RNAs (circRNAs) exert vital functions in glioma pathogenesis. CircRNA ubiquitin-associated protein 2 (circ-UBAP2, hsa_circ_0008344) has been illuminated as a tumor driver in glioma. Nevertheless, the mechanisms underlying the oncogenic regulation of circ-UBAP2 in glioma are still undefined. METHODS: Circ-UBAP2, miR-1205, miR-382, and GPRC5A were quantified using qRT-PCR and western blot. Cell viability was detected using a CCK-8 assay. Cell migration and invasion were measured using the would-healing and transwell assays. Flow cytometry and colony formation assay were applied to evaluate cell apoptosis and colony formation, respectively. The xenograft model assays were used to examine the impact of circ-UBAP2 on tumorigenic effect in vivo. Direct relationships among circ-UBAP2, miR-1205, miR-382, and GPRC5A were confirmed using dual-luciferase reporter assays. RESULTS: Circ-UBAP2 expression was upregulated in glioma. The reduced level of circ-UBAP2 hampered cell proliferation, migration, invasion, and enhanced apoptosis in vitro and weakened tumor growth in vivo. Mechanistically, circ-UBAP2 directly bound to miR-1205 and miR-382. miR-1205 and miR-382 mediated the regulation of circ-UBAP2 silencing on glioma cell behaviors. Moreover, GPRC5A was a functional target of miR-1205 and miR-382 in regulating glioma cell behaviors. Furthermore, circ-UBAP2 mediated GPRC5A expression through miR-1205 or miR-382 in glioma cells. CONCLUSION: Our current findings identified that circ-UBAP2 silencing impeded glioma malignant progression partially by downregulating GPRC5A through targeting miR-1205 and miR-382.

Proteome dynamics at broken replication forks reveal a distinct ATM-directed repair response suppressing DNA double-strand break ubiquitination.

Cells have evolved an elaborate DNA repair network to ensure complete and accurate DNA replication. Defects in these repair machineries can fuel genome instability and drive carcinogenesis while creating vulnerabilities that may be exploited in therapy. Here, we use nascent chromatin capture (NCC) proteomics to characterize the repair of replication-associated DNA double-strand breaks (DSBs) triggered by topoisomerase 1 (TOP1) inhibitors. We reveal profound changes in the fork proteome, including the chromatin environment and nuclear membrane interactions, and identify three classes of repair factors according to their enrichment at broken and/or stalled forks. ATM inhibition dramatically rewired the broken fork proteome, revealing that ataxia telangiectasia mutated (ATM) signalling stimulates DNA end resection, recruits PLK1, and concomitantly suppresses the canonical DSB ubiquitination response by preventing accumulation of RNF168 and BRCA1-A. This work and collection of replication fork proteomes provide a new framework to understand how cells orchestrate homologous recombination repair of replication-associated DSBs.

circRNA-UBAP2 promotes the proliferation and inhibits apoptosis of ovarian cancer though miR-382-5p/PRPF8 axis.

OBJECTIVE: circular RNAs (circRNAs) have been reported to be essential regulators of multiple malignant cancers. However, the functions of circRNAs in ovarian cancer need to be further explored. The aim of our study is to explore the role of circRNA-UBAP2 in ovarian cancer and its mechanism. RESULTS: circRNA-UBAP2 was upregulated in ovarian cancer tissues and cell lines. Knockdown of circRNA-UBAP2 inhibited cell proliferation and promoted cell apoptosis, but circRNA-UBAP2 overexpressed got opposite results. In addition, circRNA-UBAP2 targeted miR-382-5p and downregulated its expression, PRPF8 was a target gene of miR-382-5p. Furthemore, circRNA-UBAP2/miR-382-5p/PRPF8 axis affected the proliferation, apoptosis and cell cycle of ovarian cancer through the mechanism of competing endogenous RNAs (ceRNA). CONCLUSION: circRNA-UBAP2 acted as a ceRNA to sponged miR-382-5p, increased the expression level of PRPF8, and prompted proliferation and inhibited apoptosis in ovarian cancer cells.

Ubiquitin-binding associated protein 2 regulates KRAS activation and macropinocytosis in pancreatic cancer.

Macropinocytosis supports the metabolic requirement of RAS-transformed pancreatic ductal adenocarcinoma cells (PDACs). However, regulators of RAS-transformation (activation) that lead to macropinocytosis have not been identified. Herein, we report that UBAP2 (ubiquitin-binding associated protein 2), regulates the activation of KRAS and macropinocytosis in pancreatic cancer. We demonstrate that UBAP2 is highly expressed in both pancreatic cancer cell lines and tumor tissues of PDAC patients. The expression of UBAP2 is associated with poor overall survival in several cancers, including PDAC. Silencing UBAP2 decreases the levels of activated KRAS, and inhibits macropinocytosis, and tumor growth in vivo. Using a UBAP2-deletion construct, we demonstrate that the UBA-domain of UBAP2 is critical for the regulation of macropinocytosis and maintaining the levels of activated KRAS. In addition, UBAP2 regulates RAS downstream signaling and helps maintain RAS in the GTP-bound form. However, the exact mechanism by which UBAP2 regulates KRAS activation is unknown and needs further investigation. Thus, UBAP2 may be exploited as a potential therapeutic target to inhibit macropinocytosis and tumor growth in activated KRAS-driven cancers.

Circular RNA hsa_circ_0003141 promotes tumorigenesis of hepatocellular carcinoma via a miR-1827/UBAP2 axis.

Circular RNAs (circRNAs) play an important role in the tumorigenesis of hepatocellular carcinoma (HCC), but their specific functions in HCC remain largely unknown. Using bioinformatics analysis, we have found that the expression of circRNA hsa_circ_0003141 is significantly increased in HCC tissues. Ubiquitin-associated protein 2 (UBAP2) is the parent gene for hsa_circ_0003141, and its high expression correlates with poor overall survival rates in HCC patients. In addition, our results show that miR-1827 is a binding target of hsa_circ_0003141, and indicate that hsa_circ_0003141 regulates UBAP2 expression by sponging miR-1827 in HCC cells. Downregulation of hsa_circ_0003141 suppresses UBAP2 expression, induces apoptosis, and inhibits proliferation and invasion by HCC Huh-7 cells. Importantly, downregulation of hsa_circ_0003141 inhibits tumorigenesis in a xenograft mouse model of HCC. Together, our results indicate that hsa_circ_0003141 functions as an oncogene in HCC cells, and suggest that the hsa_circ_0003141/miR-1827/UBAP2 axis might represent a novel therapeutic option for the treatment of HCC.