Genomic binding and regulation of gene expression by the thyroid carcinoma-associated PAX8-PPARG fusion protein

Zhang, Yanxiao; Yu, Jie; Lee, Chee Khoon; Xu, Bin; Sartor, Maureen A.; Koenig, Ronald J.

doi:10.18632/oncotarget.6340

Cited by 20 publications

(25 citation statements)

References 36 publications

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“…However, the results of this mouse thyroid gland ChIP-seq are highly concordant with a ChIP-seq dataset that we previously published on PPFP stably expressed in the PCCL3 rat thyroid cell line [11], which supports the validity of both models. For example, both ChIP-seq studies showed enrichment of PPFP peaks within 1 kb of TSS’s, and both showed that most peaks contain a PAX8 motif and/or a PPARG motif near the peak center, indicating that both DBDs within PPFP are functional.…”

Section: Discussionsupporting

confidence: 88%

Genomic binding of PAX8-PPARG fusion protein regulates cancer-related pathways and alters the immune landscape of thyroid cancer

Zhang

Grachtchouk

et al. 2016

Oncotarget

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PAX8-PPARG fusion protein (PPFP) results from a t(2;3)(q13;p25) chromosomal translocation, is found in 30% of follicular thyroid carcinomas, and demonstrates oncogenic capacity in transgenic mice. A PPARG ligand, pioglitazone, is highly therapeutic in mice with PPFP thyroid cancer. However, only limited data exist to characterize the binding sites and oncogenic function of PPFP, or to explain the observed therapeutic effect of pioglitazone. Here we used our previously characterized transgenic mouse model of PPFP follicular thyroid carcinoma to identify PPFP binding sites in vivo using ChIP-seq, and to distinguish genes and pathways regulated directly or indirectly by PPFP with and without pioglitazone treatment via integration with RNA-seq data. PPFP bound to DNA regions containing the PAX8 and/or the PPARG motif, near genes involved in lipid metabolism, the cell cycle, apoptosis, and cell motility; the binding site distribution was highly concordant with our previous study in a rat PCCL3 cell line. Most strikingly, pioglitazone induced an immune cell infiltration including macrophages and T cells only in the presence of PPFP, which may be central to its therapeutic effect.

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Section: Discussionsupporting

confidence: 88%

Genomic binding of PAX8-PPARG fusion protein regulates cancer-related pathways and alters the immune landscape of thyroid cancer

Zhang

Grachtchouk

et al. 2016

Oncotarget

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“…As these drugs are already in clinical or preclinical use, expedient translation to the clinic is possible. The findings presented in this study may also have broader significance beyond GCT, specifically for malignancies that coexpress these proteins such as epithelial ovarian cancer (48,49), colorectal cancer (50), and thyroid cancer (51,52).…”

Section: Discussionmentioning

confidence: 79%

Combined PPARγ Activation and XIAP Inhibition as a Potential Therapeutic Strategy for Ovarian Granulosa Cell Tumors

Leung

Nguyen

Oliver

et al. 2019

Molecular Cancer Therapeutics

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Ovarian granulosa cell tumors (GCT) are characterized by indolent growth and late relapse. No therapeutic modalities aside from surgery have proven effective. We previously reported overexpression of the nuclear receptor, peroxisome proliferator-activated receptor-gamma (PPARg), and constitutive activity of the NFkB and AP1 signaling pathways in GCT. PPARg presents as a potential therapeutic target as it impedes proliferation and promotes terminal differentiation of granulosa cells. However, resistance to the actions of PPARg is caused by NFkB transrepression in GCTderived cell lines, KGN and COV434. We showed that abrogation of NFkB signaling in GCT cells enables PPARg agonists to initiate apoptosis. In addition, we observed overexpression of an NFkB-induced gene, X-linked inhibitor of apoptosis protein (XIAP), in GCT and GCT-derived cells. XIAP is an attractive therapeutic target due to its role in inhibiting the apoptotic pathway. We investigated the antitumor effects of combined XIAP inhibition using Smacmimetics and PPARg activation using thiazolidinediones (TZD) in the GCT-derived cells. Transactivation assays revealed that NFkB transrepression of PPARg can be relieved by NFkB or XIAP inhibition. Combined Smac-mimetic and TZD significantly induced apoptosis, reduced cell viability and proliferation in KGN cells in monolayer and 3D spheroid culture, and in GCT explant models. The Smac-mimetic and TZD cotreatment also delayed cell invasion, upregulated proapoptotic genes, and compromised cell metabolism in KGN cells. This study provides evidence that PPARg and XIAP cotreatment has antineoplastic effects in GCT. As therapeutics that target these proteins are already in clinical or preclinical use, expedient translation to the clinic is possible.

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“…However, the mechanisms involved in tumorigenesis and progression remains unclear. Unlike other driver mutations in thyroid cancers that overexpress kinase signaling pathways, PAX8-PPARG gene fusion involves tumor immunology and several cancer-related pathways such as apoptosis, cell cycle, and motility [82].…”

Section: Follicular Thyroid Cancer (Ftc)mentioning

confidence: 99%

Multi-omics Signatures and Translational Potential to Improve Thyroid Cancer Patient Outcome

Boufraqech

Nilubol

2019

Cancers

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Recent advances in high-throughput molecular and multi-omics technologies have improved our understanding of the molecular changes associated with thyroid cancer initiation and progression. The translation into clinical use based on molecular profiling of thyroid tumors has allowed a significant improvement in patient risk stratification and in the identification of targeted therapies, and thereby better personalized disease management and outcome. This review compiles the following: (1) the major molecular alterations of the genome, epigenome, transcriptome, proteome, and metabolome found in all subtypes of thyroid cancer, thus demonstrating the complexity of these tumors and (2) the great translational potential of multi-omics studies to improve patient outcome.

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Genomic binding and regulation of gene expression by the thyroid carcinoma-associated PAX8-PPARG fusion protein

Cited by 20 publications

References 36 publications

Genomic binding of PAX8-PPARG fusion protein regulates cancer-related pathways and alters the immune landscape of thyroid cancer

Genomic binding of PAX8-PPARG fusion protein regulates cancer-related pathways and alters the immune landscape of thyroid cancer

Combined PPARγ Activation and XIAP Inhibition as a Potential Therapeutic Strategy for Ovarian Granulosa Cell Tumors

Multi-omics Signatures and Translational Potential to Improve Thyroid Cancer Patient Outcome

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