Chromatin remodelers HELLS and UHRF1 mediate the epigenetic deregulation of genes that drive retinoblastoma tumor progression.
Chromatin remodelers HELLS and UHRF1 mediate the epigenetic deregulation of genes that drive retinoblastoma tumor progression.
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DOI：
10.18632/oncotarget.2468
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发表时间：
2014-10-30
期刊：
影响因子：
--
通讯作者：
Dyer MA
中科院分区：
文献类型：
--
作者：
Benavente CA;Finkelstein D;Johnson DA;Marine JC;Ashery-Padan R;Dyer MA
视网膜母细胞瘤（Rb）蛋白家族是发育过程中细胞周期退出的关键调节因子，其失调与癌症有关。Rb对视网膜正常发育至关重要，生殖系突变导致视网膜母细胞瘤，使视网膜成为研究Rb家族信号传导的一个有吸引力的系统。Rb通过转录因子E2f家族协调增殖和分化，这是Rb在视网膜发育和肿瘤发生中的重要相互作用。然而，不同的E2fs在控制视网膜发育和肿瘤发生中的作用是否可以互换，或者它们是否具有选择性功能仍然未知。在本研究中，我们发现E2f家族成员在肿瘤的发展和发生中发挥着不同的作用。Rb;p107缺陷视网膜，E2f1和E2f3失活挽救肿瘤形成，但只有E2f1挽救视网膜发育表型。这使得确定Rb/E2f家族信号的关键靶基因有助于肿瘤发生和那些有助于发育缺陷。我们发现Sox4和Sox11基因与发育表型有关，Hells和Uhrf1基因与肿瘤发生有关。通过原位人类异种移植物，我们证实了HELLS和UHRF1的上调对肿瘤表型至关重要。此外，这些表观遗传调控因子对SYK的调控也很重要。
The retinoblastoma (Rb) family of proteins are key regulators of cell cycle exit during development and their deregulation is associated with cancer. Rb is critical for normal retinal development and germline mutations lead to retinoblastoma making retinae an attractive system to study Rb family signaling. Rb coordinates proliferation and differentiation through the E2f family of transcription factors, a critical interaction for the role of Rb in retinal development and tumorigenesis. However, whether the roles of the different E2fs are interchangeable in controlling development and tumorigenesis in the retina or if they have selective functions remains unknown. In this study, we found that E2f family members play distinct roles in the development and tumorigenesis. In Rb;p107-deficient retinae, E2f1 and E2f3 inactivation rescued tumor formation but only E2f1 rescued the retinal development phenotype. This allowed the identification of key target genes for Rb/E2f family signaling contributing to tumorigenesis and those contributing to developmental defects. We found that Sox4 and Sox11 genes contribute to the developmental phenotype and Hells and Uhrf1 contribute to tumorigenesis. Using orthotopic human xenografts, we validated that upregulation of HELLS and UHRF1 is essential for the tumor phenotype. Also, these epigenetic regulators are important for the regulation of SYK.
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影响因子：
11.2
作者：
Brennan RC;Federico S;Bradley C;Zhang J;Flores-Otero J;Wilson M;Stewart C;Zhu F;Guy K;Dyer MA
通讯作者：
Dyer MA
影响因子：
--
作者：
Benavente CA;McEvoy JD;Finkelstein D;Wei L;Kang G;Wang YD;Neale G;Ragsdale S;Valentine V;Bahrami A;Temirov J;Pounds S;Zhang J;Dyer MA
通讯作者：
Dyer MA
影响因子：
2.5
作者：
Johnson, Dianna A.;Donovan, Stacy L.;Dyer, Michael A.
通讯作者：
Dyer, Michael A.
影响因子：
5.3
作者：
Magri, Laura;Swiss, Victoria A.;Casaccia, Patrizia
通讯作者：
Casaccia, Patrizia
影响因子：
11.2
作者：
Scharer, Christopher D.;McCabe, Colleen D.;Ali-Seyed, Mohamed;Berger, Michael F.;Bulyk, Martha L.;Moreno, Carlos S.
通讯作者：
Moreno, Carlos S.