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GATA zinc finger protein p66β promotes breast cancer cell migration by acting as a co-activator of Snail.

ABSTRACT: The transcriptional repressor Snail induces EMT during embryonic development and tumor metastasis. Growing evidence indicates that Snail functions as a trans-activator to induce gene expression; however, the underlying mechanism remains elusive. Here, we report that Snail cooperates with GATA zinc finger protein p66β to transactivate genes in breast cancer cells. Biologically, depletion of p66β reduces cell migration and lung metastasis in BALB/c mice. Mechanistically, Snail interacts with p66β and cooperatively induces gene transcription. Notably, a group of genes induced by Snail harbor conserved G-rich cis-elements (5'-GGGAGG-3', designated as G-box) in their proximal promoter regions. Snail directly binds to G-box via its zinc fingers and transactivates the G-box-containing promoters. p66β enhances Snail binding affinity to G-box, whereas depletion of p66β results in a decreased binding affinity of Snail to the endogenous promoters and concomitantly reduces the transcription of Snail-induced genes. Taken together, these data demonstrated that p66β is critical for Snail-mediated cell migration by acting as a co-activator of Snail to induce genes containing G-box elements in the promoters.

SUBMITTER: Zou X

PROVIDER: S-EPMC10307831 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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GATA zinc finger protein p66β promotes breast cancer cell migration by acting as a co-activator of Snail.

Zou Xiuqun X Ma Li L Zhang Yihong Y Zhang Qun Q Xu Chu C Zhang Dan D Chu Yimin Y Zhang Jie J Li Mengying M Zhang Hui H Wang Jiamin J Peng Chicheng C Wei Gang G Wu Yingjie Y Hou Zhaoyuan Z Jia Hao H

Cell death & disease 20230628 6

The transcriptional repressor Snail induces EMT during embryonic development and tumor metastasis. Growing evidence indicates that Snail functions as a trans-activator to induce gene expression; however, the underlying mechanism remains elusive. Here, we report that Snail cooperates with GATA zinc finger protein p66β to transactivate genes in breast cancer cells. Biologically, depletion of p66β reduces cell migration and lung metastasis in BALB/c mice. Mechanistically, Snail interacts with p66β ...[more]

PMID: 37380643

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Project description:We identified that GATA zinc finger domain containing 1 (GATAD1), a transcriptional factor, was significantly up-regulated in hepatocellular carcinoma (HCC) through gene amplification. We demonstrated the critical role, molecular mechanisms, and clinical implications of GATAD1 as a novel oncogenic factor in HCC. We found that GATAD1 protein was expressed in 76.6% of primary HCCs (85/111) but silenced in normal liver tissues. Gene amplification of GATAD1 was positively correlated with its overexpression in primary HCCs (R = 0.629, P < 0.0001). GATAD1 significantly increased cell proliferation, G1 -S cell cycle transition, and migration/invasion but suppressed apoptosis in liver cell lines and promoted tumor growth and lung metastasis in both xenograft and orthotopic mouse models. Mechanistically, GATAD1 induced the transcriptional expression of phosphatase of regenerating liver 3 (PRL3) by binding to its promoter identified by RNA sequencing and chromatin immunoprecipitation-PCR analyses. PRL3 played an oncogenic role in HCC. Knockdown of PRL3 blunted the tumorigenic effect of GATAD1. In addition, GATAD1 activated Akt signaling, evidenced by increased phosphorylation levels of total Akt, Akt1, Akt2, and Akt target glycogen synthase kinase 3β, while knockdown of PRL3 abolished this effect of GATAD1. We further unveiled that PRL3 activated Akt signaling by dephosphorylating phosphatase and tensin homolog at tyrosine residue, thus reducing phosphatase and tensin homolog protein. The PRL3 inhibitor 5-[[5-bromo-2-[(2-bromophenyl)methoxy]phenyl]methylene]-2-thioxo-4-thiazolidinone significantly suppressed HCC growth by inhibiting Akt activation. Moreover, high GATAD1 nuclear protein expression was associated with poor survival of HCC patients as an independent prognostic factor.ConclusionGATAD1 plays a pivotal oncogenic role in HCC by directly inducing PRL3 transcription to activate the Akt signaling pathway. GATAD1 may serve as an independent poor prognostic factor for HCC patients. (Hepatology 2018;67:2302-2319).

Dataset Information

GATA zinc finger protein p66β promotes breast cancer cell migration by acting as a co-activator of Snail.

Publications

GATA zinc finger protein p66β promotes breast cancer cell migration by acting as a co-activator of Snail.

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