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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE200897 | GEO | 2022/04/22

REPOSITORIES: GEO

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

Project description: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.

2023-03-29 | PXD040806 | Pride

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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

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

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

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

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