PAX8 and MECOM are interaction partners driving ovarian cancer.
PAX8 and MECOM are interaction partners driving ovarian cancer.
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DOI：
10.1038/s41467-021-22708-w
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发表时间：
2021-04-26
影响因子：
16.6
通讯作者：
Galli GG
中科院分区：
文献类型：
--
作者：
Bleu M;Mermet-Meillon F;Apfel V;Barys L;Holzer L;Bachmann Salvy M;Lopes R;Amorim Monteiro Barbosa I;Delmas C;Hinniger A;Chau S;Kaufmann M;Haenni S;Berneiser K;Wahle M;Moravec I;Vissières A;Poetsch T;Ahrné E;Carte N;Voshol J;Bechter E;Hamon J;Meyerhofer M;Erdmann D;Fischer M;Stachyra T;Freuler F;Gutmann S;Fernández C;Schmelzle T;Naumann U;Roma G;Lawrenson K;Nieto-Oberhuber C;Cobos-Correa A;Ferretti S;Schübeler D;Galli GG
转录因子PAX 8对甲状腺和泌尿生殖系统的发育至关重要。全面的基因组筛选进一步表明PAX 8在肾癌和卵巢癌中的额外致癌作用。虽然已经提出了在不同背景下的PAX 8调控基因，但我们仍然缺乏对PAX 8如何参与分子复合物以驱动疾病相关致癌转录程序的机制理解。在这里，我们表明，源自MECOM基因座的蛋白质亚型与PAX 8形成复合物。这些包括MDS 1-EVI 1（也称为PRDM 3），我们在体外和体内绘制了其与PAX 8的相互作用。我们发现PAX 8结合了大量的基因组位点并形成了转录枢纽。在这些的子集中，PAX 8与PRDM 3一起调节参与粘附和细胞外基质的特定基因表达模块。该基因模块在细胞系、患者来源的异种移植物（PDX）和临床病例的大规模分析中与PAX 8和MECOM表达相关，并将预后较差的妇科癌症病例分层。PRDM 3在卵巢癌中扩增，我们表明MECOM基因座和PAX 8维持体内肿瘤生长，进一步支持MECOM基因座的鉴定功能是卵巢癌中PAX 8驱动的致癌功能的基础。谱系限制性转录因子PAX 8在卵巢癌细胞中致癌。在这里，作者表明PAX 8相互作用并招募MECOM基因座PRDM 3的剪接变体，以控制参与粘附和细胞外基质的基因表达模块，从而促进卵巢肿瘤发生。
The transcription factor PAX8 is critical for the development of the thyroid and urogenital system. Comprehensive genomic screens furthermore indicate an additional oncogenic role for PAX8 in renal and ovarian cancers. While a plethora of PAX8-regulated genes in different contexts have been proposed, we still lack a mechanistic understanding of how PAX8 engages molecular complexes to drive disease-relevant oncogenic transcriptional programs. Here we show that protein isoforms originating from the MECOM locus form a complex with PAX8. These include MDS1-EVI1 (also called PRDM3) for which we map its interaction with PAX8 in vitro and in vivo. We show that PAX8 binds a large number of genomic sites and forms transcriptional hubs. At a subset of these, PAX8 together with PRDM3 regulates a specific gene expression module involved in adhesion and extracellular matrix. This gene module correlates with PAX8 and MECOM expression in large scale profiling of cell lines, patient-derived xenografts (PDXs) and clinical cases and stratifies gynecological cancer cases with worse prognosis. PRDM3 is amplified in ovarian cancers and we show that the MECOM locus and PAX8 sustain in vivo tumor growth, further supporting that the identified function of the MECOM locus underlies PAX8-driven oncogenic functions in ovarian cancer. Lineage-restricted transcription factor PAX8 is oncogenic in ovarian cancer cells. Here the authors show that PAX8 interacts and recruits a splice variant of the MECOM locus PRDM3 to control the gene expression module involved in adhesion and extracellular matrix, and consequently promotes ovarian tumorigenesis.
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