Predicting master transcription factors from pan-cancer expression data

Reddy, Josina C.; Fonseca, Marcos A. S.; Fuente, Rosario Corona de la; Nameki, Robbin; Dezem, Felipe Segato; Klein, I.; Chang, Heidi; Chaves-Moreira, Daniele; Afeyan, Lena K.; Malta, Tathiane M.; Lin, Xianzhi; Abbasi, Forough; Font-Tello, Alba; Sabedot, Thaís; Cejas, Paloma; Rodríguez-Malavé, Norma I.; Seo, Ji-Heui; Lin, De–Chen; Matulonis, Ursula A.; Karlan, Beth Y.; Gayther, Simon A.; Paşaniuc, Bogdan; Gusev, Alexander; Noushmehr, Houtan; Long, Henry W.; Freedman, Matthew L.; Drapkin, Ronny; Young, Richard A.; Abraham, Brian J.; Lawrenson, Kate

doi:10.1126/sciadv.abf6123

Cited by 46 publications

(51 citation statements)

References 94 publications

(142 reference statements)

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“…At the protein level, PAX8 knockdown led to an almost complete disappearance of SOX17, and SOX17 knockdown led to a substantial decrease in PAX8 levels. These results are consistent with our previously reported findings that PAX8 and SOX17 are master transcription factors that occupy regulatory elements related to their own encoding genes in ovarian cancer ( 45 ). Globally, PAX8 and SOX17 genomic binding sites colocalize within candidate active enhancers in HGSOC cell lines.…”

Section: Discussionsupporting

confidence: 94%

“…Globally, PAX8 and SOX17 genomic binding sites colocalize within candidate active enhancers in HGSOC cell lines. In addition, PAX8 binds near the SOX17 gene locus, which confirms the coregulation observed in SOX17 transcript and protein levels (45). Our transcriptomic and proteomic analyses revealed that PAX8 and SOX17 commonly regulate a family of genes associated with blood vessel formation, suggesting a cooperative role in orchestrating an important proangiogenic transcriptional program in ovarian cancer.…”

Section: Discussionsupporting

confidence: 80%

“…Transcriptome analysis of OVCAR4 cells after PAX8, SOX17, or simultaneous knockdown has been described previously ( 45 ). Briefly, ovarian carcinoma cells had their RNA chemically purified using the Nucleospin RNA Plus Kit (Macherey-Nagel, 740984.50) as recommended by the manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

“…We analyzed our previously reported ChIP-seq data for SOX17 and PAX8 ( 45 ) for binding of these transcription factors in the proximity of SERPINE1, and enhancer interactions were predicted using the GeneHancer database ( 31 ).…”

Section: Methodsmentioning

confidence: 99%

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The transcription factor PAX8 promotes angiogenesis in ovarian cancer through interaction with SOX17

et al. 2022

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PAX8 is a master transcription factor that is essential during embryogenesis and promotes neoplastic growth. It is expressed by the secretory cells lining the female reproductive tract, and its deletion during development results in atresia of reproductive tract organs. Nearly all ovarian carcinomas express PAX8, and its knockdown results in apoptosis of ovarian cancer cells. To explore the role of PAX8 in these tissues, we purified the PAX8 protein complex from nonmalignant fallopian tube cells and high-grade serous ovarian carcinoma cell lines. We found that PAX8 was a member of a large chromatin remodeling complex and preferentially interacted with SOX17, another developmental transcription factor. Depleting either PAX8 or SOX17 from cancer cells altered the expression of factors involved in angiogenesis and functionally disrupted tubule and capillary formation in cell culture and mouse models. PAX8 and SOX17 in ovarian cancer cells promoted the secretion of angiogenic factors by suppressing the expression of SERPINE1 , which encodes a proteinase inhibitor with anti a ngiogenic effects. The findings reveal a non–cell-autonomous function of these transcription factors in regulating angiogenesis in ovarian cancer.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 80%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The transcription factor PAX8 promotes angiogenesis in ovarian cancer through interaction with SOX17

et al. 2022

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“…Recent studies indicated that SOX17 may be involved in tumorigenesis, and TCGA has recently classi ed SOX17 as a mutated cancer driver gene in endometrial carcinoma (29)(30)(31)(32). Both SOX17 and PAX8 might be involved in tumorigenesis from ovarian and endometrial origins, and PAX8 promotes angiogenesis in ovarian cancer through interaction with SOX17 (33,34). Interestingly, multiple studies show SOX17 may function as a tumor suppressor in endometrial cancer and many other cancer types through inhibiting the WNT/beta-catenin oncogenic pathway, and hypermethylation of SOX17 has been linked to it repression in breast, colon, stomach, liver, and lung cancer (35)(36)(37)(38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

SOX17: a highly sensitive and specific marker for ovarian and endometrial carcinomas

Zhang

Niu

et al. 2022

Preprint

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A major challenge in diagnostic pathology is to identify sensitive and specific markers for tumor origin. Although PAX8 is the most widely used marker for gynecological tumors, it is not entirely specific, which makes it difficult to determine the origin of some tumors with high confidence. Through mining The Cancer Genome Atlas mRNA expression profile data, we identified SOX17 as a potential specific marker at the mRNA level for gynecological tumors. To test SOX17 expression at the protein level, we performed immunochemical staining in a large cohort of ovarian and endometrial cancer cases (n = 402) together with a large cohort of solid tumors from other organs (n = 1269). Similar to PAX8, SOX17 was highly expressed in all subtypes of ovarian carcinoma (97.5% for SOX17 vs. 97% for PAX8 in serous, 90% vs. 90% in endometrioid, and 100% vs. 100% in clear cell and transitional cell types) except for mucinous carcinoma (0% vs 27%), and also highly expressed in endometrial endometrioid carcinoma (88% vs 84%). However, SOX17 was completely negative in thyroid carcinoma and renal cell carcinoma, whereas PAX8 expression was high (86% and 85%, respectively). In addition, SOX17 had no expression in breast carcinoma, lung carcinoma, pancreatic adenocarcinoma, colonic and gastric adenocarcinomas, salivary ductal carcinoma, hepatocellular carcinoma, and cholangiocarcinoma. Our data indicate that SOX17 is not only a sensitive but also a specific marker for the origin of ovarian and endometrial carcinomas.

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Roles of non-coding RNAs in the metabolism and pathogenesis of bladder cancer

Sanya

Onésime

2023

Human Cell

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Predicting master transcription factors from pan-cancer expression data

Abstract: The CaCTS algorithm nominates cancer cell master transcription factors and guides a model of ovarian cancer regulatory circuitry.

Cited by 46 publications

References 94 publications

The transcription factor PAX8 promotes angiogenesis in ovarian cancer through interaction with SOX17

The transcription factor PAX8 promotes angiogenesis in ovarian cancer through interaction with SOX17

SOX17: a highly sensitive and specific marker for ovarian and endometrial carcinomas

Roles of non-coding RNAs in the metabolism and pathogenesis of bladder cancer

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