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Molecular Mediator of Prostate Cancer Progression and Its Implication in Therapy
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Samikshan Dutta, Navatha Shree Sharma, Ridwan Islam, Kaustubh Datta
Down-regulation of the NKX3.1 homeobox gene is a frequent event in prostate cancer and is likely to involve multiple mechanisms [100]. Loss-of-heterozygosity (LOH) of NKX3.1 at chromosome 8p21.2 occurs in nearly 85% of high-grade PIN lesions and adenocarcinomas [101–105]. However, although LOH of 8p21 progressively increases in frequency with cancer grade, the remaining allele of NKX3.1 remains as wild type [102, 105–107]. In addition, there is substantial evidence that NKX3.1 undergoes epigenetic down-regulation especially during later stages of prostate cancer progression, probably through its promoter methylation [108]. During development, NKX3.1 is expressed in all epithelial cells of the nascent prostate buds from the urogenital sinus, and represents the earliest known marker for the prostate epithelium [109]. In the absence of NKX3.1, there is a significant decrease in prostatic ductal branching, as well as in production of secretory proteins [109–111]. Notably, young adult mice with NKX3.1 heterozygous and homozygous mutants frequently display prostate epithelial hyperplasia and dysplasia, and often develop intraductal neoplasia (PIN) by 1 year of age [109–113]. These findings are consistent with the tumor suppressor activity of NKX3.1 in cell culture and xenograft assays [113, 114]. Analyses of NKX3.1 function in human tumor cells and genetically engineered mice have provided insights into its potential roles in cancer. In particular, NKX3.1 inactivation in mice results in a defective response to oxidative damage, while its expression in human prostate cancer cell lines protects against DNA damage and is regulated by inflammation [100, 115–117]. Although earlier studies had suggested that NKX3.1 expression is completely lost in advanced cancers, recent analyses using a highly sensitive antibody indicate that low levels of NKX3.1 expression can be demonstrated in nearly all prostate cancers and metastases examined [118, 119]. Thus, there appears to be a selection for reduction, but not loss, of NKX3.1 expression throughout prostate cancer progression. These findings are highly suggestive, since NKX3.1 has been shown to be a critical regulator of prostate epithelial differentiation and stem cell function in mouse models. Recent work has shown that Nkx3.1 expression in the androgen-deprived prostate marks a rare population of prostate epithelial stem cells that is a cell of origin for prostate cancer in mouse models [120]. A causal role for Nkx3.1 in these processes has been suggested by analyses of genes that are dysregulated following perturbation of Nkx3.1 expression in mouse models or human cell lines [115, 121–123].
Oxidative DNA Damage-Mediated Genomic Heterogeneity Is Regulated by NKX3.1 in Prostate Cancer
Published in Cancer Investigation, 2019
Bilge Debelec-Butuner, Aykut Bostancı, Filiz Ozcan, Oznur Singin, Selda Karamil, Mutay Aslan, Dirk Roggenbuck, Kemal Sami Korkmaz
NKX3.1 is an androgen-regulated gene that encodes a homeobox protein with a tumor suppressor function in prostate cells is upregulated by androgens (3–5), and consistently its loss has been reported in prostate tumors (6). Nevertheless, the functional loss of NKX3.1 expression upon cytokine exposure has also been proven in previous studies of the inflammatory microenvironment (7, 8), supported its functional role in antioxidant regulation (9) beside its tumor suppressor role in prostate carcinogenesis.