PAX9 Determines Epigenetic State Transition and Cell Fate in Cancer

Zhao, Zibo; Szczepanski, Aileen P.; Tsuboyama, Natsumi; Abdala‐Valencia, Hiam; Goo, Young Ah; Singer, Benjamin D.; Bartom, Elizabeth T.; Yue, Feng; Wang, Lu

doi:10.1158/0008-5472.can-21-1114

Cited by 14 publications

(10 citation statements)

References 51 publications

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“…In multiple SCLC cell lines, PAX9 deletion significantly induced a primed-active enhancer transition and caused overexpression of many neural differentiation and tumor-suppressive genes. Furthermore, PAX9 was found to interact and cooperate with the nucleosome remodeling and deacetylase complex at enhancers to repress nearby gene expression [ 33 ].…”

Section: Pax9 In Specific Cancermentioning

confidence: 99%

“…As mentioned above, the rs2236007 G allele in the PAX9 promoter region increased EGR1 binding, which suppressed PAX9 expression in breast cancer cells [ 39 ]. The BAP1/ASXL3/BRD4 epigenetic axis promoted PAX9 expression in SCLC cells [ 33 ]. miR-130b, a highly expressed microRNA in ESCC, suppressed PAX9 expression in ESCC.…”

Section: Upstream Regulation Of Pax9 Expressionmentioning

confidence: 99%

“…In addition, all histone methyltransferase Suv39h-dependent heterochromatic repeat regions in the mouse genome showed a high concordance with transcription factor binding sites [ 58 ]. PAX9 also behaves as an enhancer-specific binding factor [ 33 ]. In SCLC cells, <7% of PAX9 protein occupied the promoter/TSS regions at the chromatin.…”

Section: Downstream Events Of Pax9mentioning

confidence: 99%

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PAX9 in Cancer Development

Chen

Paiboonrungruang

et al. 2022

IJMS

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Paired box 9 (PAX9) is a transcription factor of the PAX family functioning as both a transcriptional activator and repressor. Its functional roles in the embryonic development of various tissues and organs have been well studied. However, its roles and molecular mechanisms in cancer development are largely unknown. Here, we review the current understanding of PAX9 expression, upstream regulation of PAX9, and PAX9 downstream events in cancer development. Promoter hypermethylation, promoter SNP, microRNA, and inhibition of upstream pathways (e.g., NOTCH) result in PAX9 silencing or downregulation, whereas gene amplification and an epigenetic axis upregulate PAX9 expression. PAX9 may contribute to carcinogenesis through dysregulation of its transcriptional targets and related molecular pathways. In summary, extensive studies on PAX9 in its cellular and tissue contexts are warranted in various cancers, in particular, HNSCC, ESCC, lung cancer, and cervical SCC.

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Section: Pax9 In Specific Cancermentioning

confidence: 99%

Section: Upstream Regulation Of Pax9 Expressionmentioning

confidence: 99%

Section: Downstream Events Of Pax9mentioning

confidence: 99%

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PAX9 in Cancer Development

Chen

Paiboonrungruang

et al. 2022

IJMS

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“…4G, Additional file 2: Fig. S4G, H), which are all critical genes for SCLC development [17,33,34]. Finally, to determine the impact of MBD6 on SCLC tumor growth in vivo, we injected NCI-H510 human SCLC cell lines transduced with either non-targeting CRISPR-Cas9 or two distinct MBD6 sgRNAs into the right flank of nude mice.…”

Section: Mbd6 (But Not Mbd5) Is Necessary For Tumor Cell Growthmentioning

confidence: 99%

“…Moreover, we have recently characterized a human small cell lung cancer (SCLC)-specific epigenetic axis comprised of BAP1/ASXL3/BRD4 [15]. In SCLC cells, the lineage-specific scaffold subunit ASXL3 directly links BRD4 to BAP1 at active enhancers and drives oncogenic gene expression [17]. Genetic depletion of BAP1 or inhibition of BAP1 activity by small molecule inhibitors [18] could dramatically reduce the tumor growth of BAP1-dependent cancer, such as ASXL1-mutant leukemia [19], breast cancer [19], and SCLC [18].…”

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confidence: 99%

MBD5 and MBD6 stabilize the BAP1 complex and promote BAP1-dependent cancer

et al. 2022

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Background BRCA1-associated protein 1 (BAP1) is an ubiquitin carboxy-terminal hydrolase, which forms a multi-protein complex with different epigenetic factors, such as ASXL1-3 and FOXK1/2. At the chromatin level, BAP1 catalyzes the removal of mono-ubiquitination on histone H2AK119 in collaboration with other subunits within the complex and functions as a transcriptional activator in mammalian cells. However, the crosstalk between different subunits and how these subunits impact BAP1’s function remains unclear. Results We report the identification of the methyl-CpG-binding domain proteins 5 and 6 (MBD5 and MBD6) that bind to the C-terminal PHD fingers of the large scaffold subunits ASXL1-3 and stabilize the BAP1 complex at the chromatin. We further identify a novel Drosophila protein, the six-banded (SBA), as an ortholog of human MBD5 and MBD6, and demonstrate that the core modules of the BAP1 complex is structurally and functionally conserved from Drosophila (Calypso/ASX/SBA) to human cells (BAP1/ASXL/MBD). Dysfunction of the BAP1 complex induced by the misregulation/mutations in its subunit(s) are frequent in many human cancers. In BAP1-dependent human cancers, such as small cell lung cancer (SCLC), MBD6 tends to be a part of the predominant complex formed. Therefore, depletion of MBD6 leads to a global loss of BAP1 occupancy at the chromatin, resulting in a reduction of BAP1-dependent gene expression and tumor growth in vitro and in vivo. Conclusions We characterize MBD5 and MBD6 as important regulators of the BAP1 complex and maintain its transcriptional landscape, shedding light on the therapeutic potential of targeting MBD5 and MBD6 in BAP1-dependent human cancers.

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Neuroendocrine transdifferentiation in human cancer: molecular mechanisms and therapeutic targets

Jiang,

Han,

Wang

et al. 2024

MedComm

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Neuroendocrine transdifferentiation (NEtD), also commonly referred to as lineage plasticity, emerges as an acquired resistance mechanism to molecular targeted therapies in multiple cancer types, predominately occurs in metastatic epidermal growth factor receptor (EGFR)‐mutant non‐small cell lung cancer treated with EGFR tyrosine kinase inhibitors and metastatic castration‐resistant prostate cancer treated with androgen receptor targeting therapies. NEtD tumors are the lethal cancer histologic subtype with unfavorable prognosis and limited treatment. A comprehensive understanding of molecular mechanism underlying targeted‐induced plasticity could greatly facilitate the development of novel therapies. In the past few years, increasingly elegant studies indicated that NEtD tumors share key the convergent genomic and phenotypic characteristics irrespective of their site of origin, but also embrace distinct change and function of molecular mechanisms. In this review, we provide a comprehensive overview of the current understanding of molecular mechanism in regulating the NEtD, including genetic alterations, DNA methylation, histone modifications, dysregulated noncoding RNA, lineage‐specific transcription factors regulation, and other proteomic alterations. We also provide the current management of targeted therapies in clinical and preclinical practice.

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PAX9 Determines Epigenetic State Transition and Cell Fate in Cancer

Cited by 14 publications

References 51 publications

PAX9 in Cancer Development

PAX9 in Cancer Development

MBD5 and MBD6 stabilize the BAP1 complex and promote BAP1-dependent cancer

Neuroendocrine transdifferentiation in human cancer: molecular mechanisms and therapeutic targets

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