Integrative proteogenomic analyses of human tumours identifies ADNP as a novel oncogenic mediator of cell cycle progression in high-grade serous ovarian cancer with poor prognosis

Abstract

BackgroundDespite toxic side effects and limited durable response, the current standard-of-care treatment for high grade serous ovarian cancer (HGSOC) remains platinum/taxane-based chemotherapy. Given that the overall prognosis has not improved drastically over the past several decades, there is a critical need to understand the underlying mechanisms that lead to tumour development and progression.MethodsWe utilized an integrative proteogenomic analysis of HGSOC tumours applying a poor prognosis gene expression signature (PPS) as a conceptual framework to analyse orthogonal genomic and proteomic data from the TCGA (n = 488) and CPTAC (n = 169) studies. Genes identified through in silico analyses were assessed in vitro studies to demonstrate their impact on proliferation and cell cycle progression.FindingsThese analyses identified DNA amplification and overexpression of the transcription factor ADNP (Activity Dependent Neuroprotector Homeobox) in poorly prognostic tumours. Validation studies confirmed the prognostic capacity of ADNP and suggested an oncogenic role for this protein given the association between ADNP expression and pro-proliferative signalling. In vitro studies confirmed ADNP as a novel and essential mediator of cell proliferation through dysregulation of cell cycle checkpoints.InterpretationWe identified ADNP as being amplified and overexpressed in poor prognosis HGSOC in silico analyses and demonstrated that ADNP is a novel and essential oncogene in HGSOC which mediates proliferation through dysregulation of cell cycle checkpoints in vitro.FundingThe National Cancer Institute of the National Institutes of Health, the V Foundation for Cancer Research and the New Jersey Commission for Cancer Research.

ADNP Upregulation Promotes Bladder Cancer Cell Proliferation via the AKT Pathway

“…Our study shows that ADNP activated the AKT-MDM2-p53 signaling pathway, mediated the degradation of p21 and the stability of cyclin D1, and promoted the proliferation of tumor cells. Consistent with our research, a number of studies have reported that ADNP plays an important role in regulating cell growth, proliferation in some types of sarcomas and neuronal tissue as well as modulating AKT signaling pathway ( 25 ). AKT signaling also plays an important role in CD8 + T cell differentiation and regulatory T cell survival ( 37 – 39 ).…”

“…In this study, we found that the mRNA and protein expression of ADNP were upregulated compared with normal bladder urothelial tissues, and overexpression of ADNP protein was significantly associated with higher pathological grade, advanced clinical stage, and poor prognosis in BC patients. Consistent with our observations, DNA amplification and overexpression of the transcription factor ADNP were identified in high-grade and poorly prognostic ovarian cancer (25).…”

“…A study recently showed that the mice with ADNP haplo-insufficiency exhibit the decrease ability of wound healing due to the broken cell cycle progression, and the reactivation of ADNP in mouse models increased the ability of wound healing and accelerated cell cycle progression (29). Moreover, ADNP was identified to be an oncogenic mediator of cell proliferation through dysregulation of cell cycle checkpoints in high-grade serous ovarian cancer (25). In our study, flow cytometry showed that ADNP significantly accelerated transition of BC cells from G1 phase to S phase.…”

Identification of core genes for early diagnosis and the EMT modulation of ovarian serous cancer by bioinformatics perspective

“…Moreover, emerging evidence also suggests that dysregulation of cell cycle signaling cross-cascade is commonly been observed in a broad range of human cancers [ 34 , 35 ]. Especially, relevant co-DEGs were also most striking in cell cycle pathway associated highly with the tumorigenesis and progression of ovary cancer [ 36 , 37 ].…”

ADNP (Activity Dependent Neuroprotector Homeobox): A novel oncogene driving poor prognosis in high-grade serous carcinoma

“…In this issue of EBioMedicine, Gatza and colleagues show through an integrative proteogenomic analysis of publicly available datasets that amplification and overexpression of ADNP (Activity Dependent Neuroprotector Homeobox) are associated with poor prognosis in high-grade serous carcinoma (HGSC), and further demonstrate its oncogenic potential via in vitro studies [1].…”