Dataset Information

UPF1 contributes to the maintenance of endometrial cancer stem cell phenotype by stabilizing LINC00963.

ABSTRACT: Endometrial cancer stem cells (ECSCs) play a vital role in endometrial cancer (EC) metastasis, relapse, and chemoresistance. However, the molecular mechanisms that sustain ECSCs remain elusive. Here, we showed that the expression of UPF1 was upregulated in EC tissues and ECSCs and correlated with poor clinicopathological characteristics. UPF1 silencing suppressed ECSC hallmarks, such as sphere formation ability, carboplatin resistance, migration and invasion, and cell cycle progression. UPF1 regulated the behavior and fate of ECSCs by stabilizing LINC00963. LINC00963 further shares the same miRNA response element with the core transcription factor SOX2 and relieved the suppression of SOX2 by miR-508-5p in self-renewing ECSCs. Notably, inhibition of UPF1 and LINC00963 in combination severely impaired the in vivo tumorigenic potential of ECSCs. We demonstrate that the UPF1/LINC00963/miR-508-5p/SOX2 axis has potential value in modulating ECSC maintenance, chemoresistance, and tumorigenesis in EC, which highlights a novel promising target for EC treatment.

SUBMITTER: Chen H

PROVIDER: S-EPMC8940903 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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UPF1 contributes to the maintenance of endometrial cancer stem cell phenotype by stabilizing LINC00963.

Chen Hao H Ma Jian J Kong Fanfei F Song Ning N Wang Cuicui C Ma Xiaoxin X

Cell death & disease 20220322 3

Endometrial cancer stem cells (ECSCs) play a vital role in endometrial cancer (EC) metastasis, relapse, and chemoresistance. However, the molecular mechanisms that sustain ECSCs remain elusive. Here, we showed that the expression of UPF1 was upregulated in EC tissues and ECSCs and correlated with poor clinicopathological characteristics. UPF1 silencing suppressed ECSC hallmarks, such as sphere formation ability, carboplatin resistance, migration and invasion, and cell cycle progression. UPF1 reg ...[more]

PMID: 35318304

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Project description:BackgroundThe RNA polymerase II transcriptional Mediator subunit Med12 is broadly implicated in vertebrate brain development, and genetic variation in human MED12 is associated with X-linked intellectual disability and neuropsychiatric disorders. Although prior studies have begun to elaborate the functional contribution of Med12 within key neurodevelopmental pathways, a more complete description of Med12 function in the developing nervous system, including the specific biological networks and cellular processes under its regulatory influence, remains to be established. Herein, we sought to clarify the global contribution of Med12 to neural stem cell (NSC) biology through unbiased transcriptome profiling of mouse embryonic stem (ES) cell-derived NSCs following RNAi-mediated Med12 depletion.ResultsA total of 240 genes (177 up, 73 down) were differentially expressed in Med12-knockdown versus control mouse NS-5 (mNS-5) NSCs. Gene set enrichment analysis revealed Med12 to be prominently linked with "cell-to-cell interaction" and "cell cycle" networks, and subsequent functional studies confirmed these associations. Targeted depletion of Med12 led to enhanced NSC adhesion and upregulation of cell adhesion genes, including Syndecan 2 (Sdc2). Concomitant depletion of both Sdc2 and Med12 reversed enhanced cell adhesion triggered by Med12 knockdown alone, confirming that Med12 negatively regulates NSC cell adhesion by suppressing the expression of cell adhesion molecules. Med12-mediated suppression of NSC adhesion is a dynamically regulated process in vitro, enforced in self-renewing NSCs and alleviated during the course of neuronal differentiation. Accordingly, Med12 depletion enhanced adhesion and prolonged survival of mNS-5 NSCs induced to differentiate on gelatin, effects that were bypassed completely by growth on laminin. On the other hand, Med12 depletion in mNS-5 NSCs led to reduced expression of G1/S phase cell cycle regulators and a concordant G1/S phase cell cycle block without evidence of apoptosis, resulting in a severe proliferation defect.ConclusionsMed12 contributes to the maintenance of NSC identity through a functionally bipartite role in suppression and activation of gene expression programs dedicated to cell adhesion and G1/S phase cell cycle progression, respectively. Med12 may thus contribute to the regulatory apparatus that controls the balance between NSC self-renewal and differentiation, with important implications for MED12-linked neurodevelopmental disorders.

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UPF1 contributes to the maintenance of endometrial cancer stem cell phenotype by stabilizing LINC00963.

Publications

UPF1 contributes to the maintenance of endometrial cancer stem cell phenotype by stabilizing LINC00963.

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