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DNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC

ABSTRACT: Hitherto, most studies on POLD1 have mainly focused on the effect of POLD1 inactivation mutation in tumors. Nonetheless, the mechanism underlying high POLD1 expression in tumorigenesis remains elusive. Herein, we substantiated the pro-carcinogenic role of POLD1 in bladder cancer (BLCA) and found that POLD1 expression is related to malignancy and prognosis of BLCA. Next, we demonstrated that POLD1 could promote proliferation and metastasis of BLCA via MYC. Mechanistically, we demonstrated that POLD1 was able to stabilize MYC in a manner independent of DNA polymerase activity. POLD1 attenuated the FBXW7-mediated ubiquitination degradation of MYC by directly binding to the MYC homology box 1 domain competitively with FBXW7. Moreover, we found that POLD1 can form a complex with MYC to promote the transcriptional activity of MYC. MYC could also transcriptionally activate POLD1, forming a POLD1-MYC positive feedback loop to enhance the pro-carcinogenic effect of POLD1-MYC on BLCA. Overall, our study suggests a novel MYC-driven mechanism for BLCA, and POLD1 has the potential as a biomarker for BLCA.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Yejinpeng Wang

LAB HEAD: Yu Xiao

PROVIDER: PXD040806 | Pride | 2023-03-29

REPOSITORIES: Pride

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DNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC

Project description:Hitherto, most studies on DNA polymerase δ (POLD1) have mainly focused on the effect of POLD1 inactivation mutation in tumors. Nonetheless, the mechanism underlying high POLD1 expression in tumorigenesis remains elusive. Herein, we substantiated the pro-carcinogenic role of POLD1 in bladder cancer (BLCA) and found that POLD1 expression is related to malignancy and prognosis of BLCA. Next, we demonstrated that POLD1 could promote proliferation and metastasis of BLCA via MYC in vivo and in vitro. Furthermore, POLD1 and MYC were colocalized in the nucleus and co-expressed during the cell cycle. Mechanistically, we validated that POLD1 could interact directly with MYC, and POLD1 could stabilize MYC by counteracting GSK3β-mediated phosphorylation of threonine 58 and blocking the interaction between E3 ubiquitin ligase FBXW7 and MYC. Moreover, MYC could transcriptionally activate POLD1, forming a POLD1-MYC positive feedback loop to enhance the pro-carcinogenic effect of POLD1-MYC on BLCA. Overall, our study identified a novel MYC-driven oncogene POLD1, providing a potential diagnostic and therapeutic target for BLCA.

2022-04-22 | GSE200897 | GEO

Identification of novel SCF FBXW7 substrates in asynchronous and mitotic cells

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2022-12-02 | PXD035501 | Pride

Expression data from c-Myc+ Notch1 T-ALL initiating cells

Project description:Missense FBXW7 mutations are prevalent in various tumors, including T-cell acute lymphoblastic leukemia (T-ALL). To study the effects of such lesions, we generated animals carrying regulatable Fbxw7 mutant alleles. We show here that these mutations specifically bolster cancer-initiating cell activity in collaboration with Notch1 oncogenes, but spare normal hematopoietic stem cell function. We were also able to show that FBXW7 mutations specifically affect the ubiquitylation and half-life of c-Myc protein, a key T-ALL oncogene. Using animals carrying c-Myc fusion alleles, we connected Fbxw7 function to c-Myc abundance and correlated c-Myc expression to leukemia-initiating activity. Three independent Notch1 T-ALL were derived on c-Myc-GFP background and sorted from the spleen of leukemic mice on the basis of GFP expression for RNA extraction and hybridization on Affymetrix microarrays

2013-05-10 | E-GEOD-46797 | biostudies-arrayexpress

Expression data from c-Myc+ Notch1 T-ALL initiating cells

2013-05-10 | GSE46797 | GEO

Loss of Fbxw7 triggers mammary tumorigenesis associated with E2F/c-Myc activation and Trp53 mutation

Project description:Fbw7 is a tumor suppressor protein that regulates the degradation of a multitude of oncogenic substrates, such as c-Jun, c-Myc, Notch1 intracellular domain, and cyclin E. Loss of FBXW7 expression is relatively common in breast cancer. Despite this, the effect of FBXW7 loss on breast tumorigenesis has not been examined. We demonstrate here that loss of FBXW7 is sufficient for breast tumorigenesis. Many of Fbw7’s substrates are transcription factors or are closely linked to transcription factor pathways. As loss of Fbw7 results in upregulation of multiple substrates, we set out to determine which, if any of these transcription factor pathways predominate early after Fbw7 loss and after tumorigenesis. To address this, we employed genome-wide RNA sequencing to examine transcription factor pathway alterations early after FBXW7 loss in non-tumor breast epithelial cells as well as after prolonged FBXW7 loss, in tumor samples. We demonstrate an early upregulation of E2F and c-Myc pathways that is reinforced upon tumorigenesis. These findings suggest E2F and c-Myc as important targetable pathways in Fbw7 low breast cancer patients.

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Long noncoding RNA SAM promotes myoblast proliferation and skeletal muscle regeneration through stabilizing Sugt1 and facilitating kinetochore assembly

Project description:Long non-coding RNAs (lncRNAs) are novel family of gene regulators but the study of lncRNAs in satellite cell lineage progression is still at the infancy stage. Here we identified a novel lncRNA, SAM (Sugt1 associated muscle lncRNA) that was enriched in the proliferation myoblast cells but decreased as the cells progress to differentiation. Gain- or loss- of function of SAM in muscle satellite cells altered myogenic proliferation and differentiation. The above phenotypical changes in cells were also substantiated when RNAseq was performed to assess transcriptomic changes caused by SAM loss. Gene Ontology (GO) cluster analysis of up- or down-regulated genes is in line with the pro-proliferative function of SAM and the precocious differentiation upon SAM loss.

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A helicase-independent role of DHX15 promotes MYC stability and acute leukemia cell survival

Project description:DHX15 has been implicated in RNA splicing and ribosome biogenesis, primarily functioning as an RNA helicase. To systematically assess the cellular role of DHX15, we conducted proteomic analysis to investigate the landscape of DHX15 interactome, and identified MYC as a binding partner. DHX15 co-localizes with MYC in cells and directly interacts with MYC in vitro. Importantly, DHX15 contributes to MYC protein stability at the post-translational level and independent of its RNA binding capacity. Mechanistic investigation reveals that DHX15 interferes the interaction between MYC and FBXW7, thereby preventing MYC polyubiquitylation and proteasomal degradation. Consequently, abrogation of DHX15 drastically inhibits MYC-mediated transcriptional output. While DHX15 depletion blocks T-cell development and leukemia cell survival as we recently reported, overexpression of MYC significantly rescues the phenotypic defects. These findings shed new light on the essential role of DHX15 in mammalian cells and suggest that maintaining sufficient MYC expression is a significant contributor to DHX15-mediated cellular functions.

2024-01-26 | PXD046692 | Pride

Cryptococcus neoformans Hsf3 LC-MS/MS

Project description:Mitochondrial quality control is essential in modulating intramitochondrial ROS (mtROS) homeostasis that is a critical determinant for many human disorders. Here we identified an atypical function of a heat shock factor, Hsf3, as an important mtROS regulator. Despite HSFs are nuclear proteins and master regulators of protein unfolded response (UPR) across taxa, we demonstrate that Hsf3 is a both nuclei and mitochondria targeting transcription factor that plays an irrelevant function in controlling UPR process. Instead, Hsf3 represses TCA cycle genes and simultaneously regulates electron transfer chain genes encoded from both nuclei and mitochondria. Moreover, both nuclear and mitochondrial targeting signal are required for promising Hsf3 function. Hsf3 regulation responds to multiple intramitochondrial stresses, which activates and ameliorates Hsf3 DNA binding via oxidation of the cysteine residue on DNA binding domain of Hsf3. Collectively, our findings reveal a previously unknown role of HSF family in modulation of mitochondrial function and damage.

2022-09-01 | PXD033799 | Pride

A novel tumor suppressing role for RUNX3 is shown where a direct interaction with MYC leads to disruption of MYC-MAX heterodimers and consequent degradation of the MYC oncoprotein

Project description:Developmental regulator RUNX3 targets MYC protein for rapid degradation through the glycogen synthase kinase-3 beta-box/WD repeat-containing protein 7 (GSK3β-FBXW7) proteolytic pathway. We therefore uncover a previously unknown mode of MYC destabilization by RUNX3 and provide an explanation as to why RUNX3 inhibits early-stage cancer development in gastrointestinal and lung mouse cancer models.

2023-06-24 | GSE233777 | GEO

EBF1 and PAX5 control pro-B cell expansion via oppose regulation of the Myc gene

Project description:Lineage restricted transcription factors are frequently found mutated in B-lymphoid leukemia, suggesting a close link between normal and malignant B-cell development. One of these transcription factors is EBF1, a protein of critical importance for specification but also survival of B-lymphoid progenitors. We here report that impaired EBF1 function in mouse B-cell progenitors results in reduced expression of Myc. Ectopic expression of MYC rescued B-cell expansion in the absence of EBF1 both in vivo and in vitro. Using chromosome conformation analysis in combination with ATAC, ChIP-seq and reporter gene assays, identified six EBF responsive enhancer elements that could be annotated to the Myc gene. Crispr-Cas9 mediated targeting of EBF1 binding sites identified one element of importance for Myc expression and pro-B cell expansion providing evidence for that Myc is a direct target for EBF1. Furthermore, ChIP-seq analysis suggested that several regulatory elements in the Myc gene were targeted by PAX5. However, ectopic expression of PAX5 in EBF1 deficient cells was found to induce a cell cycle block and reduce Myc expression suggesting that EBF1 and PAX5 act in an opposing manner at this shared target gene. This hypothesis was further substantiated by the finding that Pax5 inactivation reduced the need for EBF1 in pro-B cell expansion. The binding of EBF1 and PAX5 to regulatory elements in the human MYC gene in a B-ALL cell line indicate that this regulatory loop may be of relevance for our understanding of both normal and malignant B-cell development.

2021-03-05 | GSE159957 | GEO

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