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Eya3 partners with PP2A to induce c-Myc stabilization and tumor progression.

ABSTRACT: Eya genes encode a unique family of multifunctional proteins that serve as transcriptional co-activators and as haloacid dehalogenase-family Tyr phosphatases. Intriguingly, the N-terminal domain of Eyas, which does not share sequence similarity to any known phosphatases, contains a separable Ser/Thr phosphatase activity. Here, we demonstrate that the Ser/Thr phosphatase activity of Eya is not intrinsic, but arises from its direct interaction with the protein phosphatase 2A (PP2A)-B55? holoenzyme. Importantly, Eya3 alters the regulation of c-Myc by PP2A, increasing c-Myc stability by enabling PP2A-B55? to dephosphorylate pT58, in direct contrast to the previously described PP2A-B56?-mediated dephosphorylation of pS62 and c-Myc destabilization. Furthermore, Eya3 and PP2A-B55? promote metastasis in a xenograft model of breast cancer, opposing the canonical tumor suppressive function of PP2A-B56?. Our study identifies Eya3 as a regulator of PP2A, a major cellular Ser/Thr phosphatase, and uncovers a mechanism of controlling the stability of a critical oncogene, c-Myc.

SUBMITTER: Zhang L

PROVIDER: S-EPMC5849647 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Eya3 partners with PP2A to induce c-Myc stabilization and tumor progression.

Zhang Lingdi L Zhou Hengbo H Li Xueni X Vartuli Rebecca L RL Rowse Michael M Xing Yongna Y Rudra Pratyaydipta P Ghosh Debashis D Zhao Rui R Ford Heide L HL

Nature communications 20180313 1

Eya genes encode a unique family of multifunctional proteins that serve as transcriptional co-activators and as haloacid dehalogenase-family Tyr phosphatases. Intriguingly, the N-terminal domain of Eyas, which does not share sequence similarity to any known phosphatases, contains a separable Ser/Thr phosphatase activity. Here, we demonstrate that the Ser/Thr phosphatase activity of Eya is not intrinsic, but arises from its direct interaction with the protein phosphatase 2A (PP2A)-B55α holoenzyme ...[more]

PMID: 29535359

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Project description:Background Osteosarcoma is the most common malignant tumor in bone and its prognosis has reached a plateau in the past few decades. Recently, metabolic reprogramming has attracted increasing attention in the field of cancer research. In our previous study, P2RX7 has been identified as an oncogene in osteosarcoma. However, whether and how P2RX7 promotes osteosarcoma growth and metastasis through metabolic reprogramming remains unexplored. Methods We used CRISPR/Cas9 genome editing technology to establish P2RX7 knockout cell lines. Transcriptomics and metabolomics were performed to explore metabolic reprogramming in osteosarcoma. RT-PCR, western blot and immunofluorescence analyses were used to determine gene expression related to glucose metabolism. Cell cycle and apoptosis were examined by flowcytometry. The capacity of glycolysis and oxidative phosphorylation were assessed by seahorse experiments. PET/CT was carried out to assess glucose uptake in vivo. Results We demonstrated that P2RX7 significantly promotes glucose metabolism in osteosarcoma via upregulating the expression of genes related to glucose metabolism. Inhibition of glucose metabolism largely abolishes the ability of P2RX7 to promote osteosarcoma progression. Mechanistically, P2RX7 enhances c-Myc stabilization by facilitating nuclear retention and reducing ubiquitination-dependent degradation. Furthermore, P2RX7 promotes osteosarcoma growth and metastasis through metabolic reprogramming in a predominantly c-Myc-dependent manner. Conclusions P2RX7 plays a key role in metabolic reprogramming and osteosarcoma progression via increasing c-Myc stability. These findings provide new evidence that P2RX7 might be a potential diagnostic and/or therapeutic target for osteosarcoma. Novel therapeutic strategies targeting metabolic reprogramming appear to hold promise for a breakthrough in the treatment of osteosarcoma. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-023-03985-z.

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Eya3 partners with PP2A to induce c-Myc stabilization and tumor progression.

Publications

Eya3 partners with PP2A to induce c-Myc stabilization and tumor progression.

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