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Capicua suppresses YAP1 to limit tumorigenesis and maintain drug sensitivity in human cancer.

ABSTRACT: Inactivation of Capicua (CIC) or upregulation of yes-associated protein 1, YAP1, leads to broad RAS-RAF-MEK-ERK inhibitor resistance and tumor progression in multiple human cancers. Despite these shared malignant phenotypes, it remains unclear whether CIC and YAP1 are mechanistically linked. Here, we show that the ERK-regulated transcription factor CIC can directly repress YAP1 expression through non-consensus GGAAGGAA DNA-binding motifs in a proximal YAP1 regulatory element. Through binding at GGAA repeats, CIC regulates YAP1 transcriptional output in both normal and human cancer cells. Silencing YAP1 in CIC-deficient cells restores MAPK inhibitor sensitivity and suppresses tumor growth. Thus, we uncover a molecular link between the MAPK-ERK effector CIC and YAP1 in human cells and established YAP inhibition as a strategy to target CIC-deficient cancers.

SUBMITTER: Kim JW

PROVIDER: S-EPMC9674208 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Capicua suppresses YAP1 to limit tumorigenesis and maintain drug sensitivity in human cancer.

Kim Ji Won JW Luck Cuyler C Wu Wei W Ponce Rovingaile Kriska RK Lin Yone Kawe YK Gupta Nehal N Okimoto Ross A RA

Cell reports 20221001 1

Inactivation of Capicua (CIC) or upregulation of yes-associated protein 1, YAP1, leads to broad RAS-RAF-MEK-ERK inhibitor resistance and tumor progression in multiple human cancers. Despite these shared malignant phenotypes, it remains unclear whether CIC and YAP1 are mechanistically linked. Here, we show that the ERK-regulated transcription factor CIC can directly repress YAP1 expression through non-consensus GGAAGGAA DNA-binding motifs in a proximal YAP1 regulatory element. Through binding at ...[more]

PMID: 36198276

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Capicua suppresses colorectal cancer progression via repression of ETV4 expression.

Project description:BackgroundAlthough major driver gene mutations have been identified, the complex molecular heterogeneity of colorectal cancer (CRC) remains unclear. Capicua (CIC) functions as a tumor suppressor in various types of cancers; however, its role in CRC progression has not been examined.MethodsDatabases for gene expression profile in CRC patient samples were used to evaluate the association of the levels of CIC and Polyoma enhancer activator 3 (PEA3) group genes (ETS translocation variant 1 (ETV1), ETV4, and ETV5), the best-characterized CIC targets in terms of CIC functions, with clinicopathological features of CRC. CIC and ETV4 protein levels were also examined in CRC patient tissue samples. Gain- and loss-of function experiments in cell lines and mouse xenograft models were performed to investigate regulatory functions of CIC and ETV4 in CRC cell growth and invasion. qRT-PCR and western blot analyses were performed to verify the CIC regulation of ETV4 expression in CRC cells. Rescue experiments were conducted using siRNA against ETV4 and CIC-deficient CRC cell lines.ResultsCIC expression was decreased in the tissue samples of CRC patients. Cell invasion, migration, and proliferation were enhanced in CIC-deficient CRC cells and suppressed in CIC-overexpressing cells. Among PEA3 group genes, ETV4 levels were most dramatically upregulated and inversely correlated with the CIC levels in CRC patient samples. Furthermore, derepression of ETV4 was more prominent in CIC-deficient CRC cells, when compared with that observed for ETV1 and ETV5. The enhanced cell proliferative and invasive capabilities in CIC-deficient CRC cells were completely recovered by knockdown of ETV4.ConclusionCollectively, the CIC-ETV4 axis is not only a key module that controls CRC progression but also a novel therapeutic and/or diagnostic target for CRC.

| S-EPMC7003492 | biostudies-literature

miR-375-3p suppresses tumorigenesis and partially reverses chemoresistance by targeting YAP1 and SP1 in colorectal cancer cells.

Project description:Clinically, one of the principal factors in the failure of advanced colorectal cancer (CRC) treatment is chemoresistance to 5-fluorouracil (5FU)-based chemotherapy. Although microRNA-375-3p (miR-375) is considered a tumor suppressor in multiple cancers, the mechanism of miR-375 in the regulation of drug resistance in CRC remains unclear. In this study, we investigated the chemosensitivity of miR-375 to 5FU in CRC from biological and clinical aspects. We found that miR-375 was significantly downregulated in CRC tissues and cell lines, and low miR-375 expression was strongly correlated with poor overall survival in CRC patients. Overexpression of miR-375 sensitized CRC cells to a broad spectrum of chemotherapeutic drugs in vitro and in vivo. Further mechanistic analysis demonstrated that miR-375 enhanced CRC cell sensitivity to 5FU by directly targeting YAP1 and SP1. MiR-375 downregulated YAP1, resulting in reduced expression of the Hippo-YAP1 pathway downstream genes CTGF, cyclin D1 and BIRC5 (also known as survivin). Overall, miR-375 was confirmed as a prospective molecular biomarker in the chemoresistance and prognosis of CRC patients, and the synergy between miR-375 and chemotherapeutic drugs could be a promising therapeutic strategy for CRC patients, especially with chemoresistance.

| S-EPMC6781994 | biostudies-literature

Targeting CDK4/6 suppresses colorectal cancer by destabilizing YAP1.

Project description:Colorectal cancer (CRC) is among the most prevalent and deadly cancers worldwide. The Yes-associated protein 1 (YAP1) is frequently dysregulated in cancers, contributing to cancer stemness, chemoresistance, and cancer-related death. However, strategies directly targeting YAP1 have not yet been successful because of the lack of active binding pockets and unregulated toxicity. In this study, our Food and Drug Administration (FDA)-approved drug screening reveals that abemaciclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, dramatically promotes the proteasome-dependent degradation of YAP1, thereby inhibiting tumor progression in CRC cells and patient-derived xenograft models. We further identify deubiquitinating enzyme 3 (DUB3) as the bona fide deubiquitinase of YAP1 in CRC. Mechanistically, CDK4/6 directly phosphorylates DUB3 at Ser41, activating DUB3 to deubiquitinate and stabilize YAP1. Conversely, loss of Ser41 phosphorylation by CDK4/6 inhibition or Ser41A mutation, promotes YAP1 degradation and suppresses YAP1-driven tumor progression. Histological analysis shows a positive correlation between DUB3 and YAP1 expression in CRC specimens. Collectively, our study uncovers a novel oncogenic role of the CDK4/6-DUB3 pathway, which promotes YAP1 stabilization and tumor-promoting function, highlighting that targeting CDK4/6 offers a potential therapeutic strategy for CRC with aberrantly upregulated DUB3 and YAP1.

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A pan-cancer landscape of centromere proteins in tumorigenesis and anticancer drug sensitivity.

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| S-EPMC10036944 | biostudies-literature

Fenofibrate Suppresses Oral Tumorigenesis via Reprogramming Metabolic Processes: Potential Drug Repurposing for Oral Cancer.

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| S-EPMC4910598 | biostudies-literature

The transcription factor RUNX2 fuels YAP1 signaling and gastric cancer tumorigenesis.

Project description:Despite considerable efforts in the detection and treatment of gastric cancer (GC), the underlying mechanism of the progression of GC remains unknown. Our previous work has demonstrated the remarkable role of Runt-related transcription factor 2 (RUNX2), in fueling the invasion and metastasis of GC. The present study aimed to elucidate the role of RUNX2 in tumorigenesis of GC. We assessed Runx2 expression and its clinical significance via bioinformatic analysis of the Cancer Genome Atlas and Gene Expression Omnibus databases. Roles for Runx2 in self-renewal and tumorigenesis were examined in vitro and in vivo. Further bioinformatic analysis was applied to study the mechanism of GC progression. We found that Runx2 was highly expressed in the early stage of GC and positively correlated with a poor clinical outcome of patients. Runx2 was also significantly correlated with clinicopathological features, such as Hp infection, new neoplastic events, primary therapeutic outcome, ethnicity, race, and tumor stage. Multivariate analysis revealed that together with Runx2, age, cancer status, M stage, and T stage were independent prognostic factors for the outcome of GC patients. RUNX2 overexpression induced increased anchorage-independent colony formation, sphere formation, and tumorigenesis in GC cells in vitro and in vivo. Mechanistically, bioinformatic analysis indicated that yes1 associated transcriptional regulator (YAP1) might be a downstream target of RUNX2. Specific knockdown of YAP1 reduced the tumor-initiating ability of GC cells induced by ectopic Runx2 expression. Our findings support the hypothesis that RUNX2 exerts oncogenic properties via YAP1 regulation, highlighting essential roles for RUNX2 and YAP1 in gastric carcinogenesis and suggesting potential therapeutic targets.

| S-EPMC8409423 | biostudies-literature

Hsa_circ_0005273 facilitates breast cancer tumorigenesis by regulating YAP1-hippo signaling pathway.

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| S-EPMC7802350 | biostudies-literature

NUSAP1 Promotes Gastric Cancer Tumorigenesis and Progression by Stabilizing the YAP1 Protein.

Project description:The Yes-associated protein (YAP1) is a main effector of the canonical Hippo pathway, which contributes greatly to tumor initiation, progression, and metastasis in multiple cancers, including gastric cancer (GC). Due to limited knowledge of YAP1 upregulation in cancer, it is a great challenge of therapeutic targets toward the Hippo-YAP1 pathway. Here, we identify nucleolar spindle-associated protein 1 (NUSAP1) as a novel binding partner of YAP1. The upregulation of NUSAP1 is associated with unfavorable clinical outcomes in GC patients, and NUSAP1 depletion impairs its oncogenic properties in vitro and in a xenograft model. Mechanistically, we discovered that NUSAP1 functions as a positive regulator of YAP1 protein stability, thereby inducing the transcription of Hippo pathway downstream target genes, such as CTGF and CYR61. More interestingly, we find that the cancer-promoting effects of NUSAP1 on GC cell growth, migration, and invasion are mainly mediated by YAP1. Furthermore, aberrant expression of NUSAP1 and YAP1 is highly correlated in GC cell lines and tissues. We herein clarify the role of the oncogenic NUSAP1-YAP1 axis in GC tumorigenesis and progression and, therefore, provide novel therapeutic targets for GC treatment.

| S-EPMC7817543 | biostudies-literature

SORBS1 suppresses tumor metastasis and improves the sensitivity of cancer to chemotherapy drug.

Project description:Tumor metastasis and invasion are both hallmarks of cancer malignancy and the leading cause of cancer death. Here we show that the adaptor protein SORBS1 (Sorbin and SH3 domain-containing protein 1, also known as CAP/ponsin) is expressed at low levels in clinical cancer samples. In addition, low-level expression of SORBS1 was significantly associated with poor clinical outcomes and the increased tumor cell invasive capacity in breast cancer patients. We demonstrate that depletion of SORBS1 increases protrusions and filopodium-like protrusions (FLPs) formation, as well as the migratory and invasive abilities of cancer cells, via activation of JNK/cJun. Furthermore, silencing of SORBS1 promotes the epithelial-to-mesenchymal transition (EMT) process and attenuates chemical drug sensitivity especially that to cisplatin, by inhibition of p53 in breast cancer cells. Thus, we illustrate that SORBS1 is a potential inhibitor of metastasis in cancer and may be a promising target in chemotherapy.

| S-EPMC5354718 | biostudies-literature

CD38 knockout suppresses tumorigenesis in mice and clonogenic growth of human lung cancer cells.

Project description:The ectodomain of the plasma membrane ectoenzyme CD38 functions as both an NAD glycohydrolase and an ADP-ribosyl cyclase by catalyzing, respectively, the conversion of NAD to nicotinamide and ADP-ribose or cyclic ADP-ribose. CD38 is attracting particular attention in cancer therapy. An anti-CD38 monoclonal antibody (daratumumab) was approved for treatment of patients with multiple myeloma. However, the role of CD38 in non-hematological malignancies has not been explored. Previously, we reported that ADP-ribose-acceptor hydrolase (ARH)-1 deficiency in mice was associated with tumor development. In the present study, we found that in wild-type and ARH1-deficient mice deletion of the CD38 gene reduced tumor formation. Significant reductions in tumor number were observed in lymphomas, adenocarcinomas and hemangio/histolytic sarcomas. Consistent with a role for CD38 in tumorigenesis, CRISPR/Cas9-based knockout of CD38 in A549 human adenocarcinoma cells inhibited anchorage-independent cell growth, cell invasion and xenograft growth in nude mice. CD38 mRNA and protein expression were evaluated in human lung cancer cell lines and in human lung cancer specimens. CD38 overexpression in tumor cells was identified in 11 of 27 patient samples. In addition, some human lung cancer cell lines had dramatically higher CD38 mRNA and protein expression than normal cells. Consistent with these observations, search of the Oncomine database showed that some human lung adenocarcinomas had higher CD38 mRNA levels compared to normal lung tissues. In total, our data are consistent with the conclusion that CD38 plays a role in murine and human lung tumorigenesis and that anti-CD38 treatment may have therapeutic potential in lung cancer.

| S-EPMC5862338 | biostudies-literature

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