ABSTRACT
Ten-eleven translocation (TET) proteins are recently characterized dioxygenases that regulate demethylation by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine and further derivatives. The recent finding that 5hmC is also a stable and independent epigenetic modification indicates that these proteins play an important role in diverse physiological and pathological processes such as neural and tumor development. Both the genomic distribution of (hydroxy)methylation and the expression and activity of TET proteins are dysregulated in a wide range of cancers including prostate cancer. Up to now it is still unknown how changes in TET and 5(h)mC profiles are related to the pathogenesis of prostate cancer. In this review, we explore recent advances in the current understanding of how TET expression and function are regulated in development and cancer. Furthermore, we look at the impact on 5hmC in prostate cancer and the potential underlying mechanisms. Finally, we tried to summarize the latest techniques for detecting and quantifying global and locus-specific 5hmC levels of genomic DNA.
Subject(s)
DNA Methylation/genetics , Prostatic Neoplasms/genetics , Proto-Oncogene Proteins/metabolism , 5-Methylcytosine/analogs & derivatives , 5-Methylcytosine/metabolism , Animals , Epigenesis, Genetic , Humans , Male , Models, Biological , Proto-Oncogene Proteins/geneticsABSTRACT
Prostate cancer progression and treatment relapse is associated with changes in the androgen receptor axis, and analysis of alternations of androgen receptor signaling is valuable for prognostics and treatment optimization. The profile of androgen receptor axis is currently obtained from biopsy specimens, which are not always easy to obtain. Moreover, the information acquired only provides a snapshot of the tumor biology, with strict spatial and temporal limitations. On the other hand, circulation is easily accessible source of both circulating tumor cells and circulating tumor DNA, which can be sampled at numerous time points. This Review will explore the potential use of androgen receptor axis alternations detectable in the blood in therapeutic decision-making and precision medicine for advancing metastatic castration-resistant prostate cancer.
Subject(s)
Liquid Biopsy/methods , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/genetics , Receptors, Androgen/metabolism , Gene Dosage , Humans , Male , Molecular Targeted Therapy , Prognosis , Prostatic Neoplasms/blood , Prostatic Neoplasms/therapy , Receptors, Androgen/blood , Receptors, Androgen/chemistry , Receptors, Androgen/geneticsABSTRACT
The androgen receptor (AR) is a ligand-inducible transcription factor. Its transcription activation domain consists of the two transcription activation units called Tau-1 and Tau- 5. Tau-5 interacts with p160 coactivators like the transcription intermediary factor 2 (TIF2), which in their turn recruit histone modifiers and chromatin-remodelling complexes. The mechanism of action of Tau-1, however, remains elusive. Here, we demonstrate that transcription intermediary factor 1ß (TIF1ß) can induce the activity of the AR up to five fold when tested in vitro. Although there is no evidence for direct interactions between TIF1ß and AR, mutation studies show that the activity of TIF1ß depends on the integrity of Tau-1 in AR on the one hand, and the so-called tripartite motif domain in TIF1ß on the other. Surprisingly, the coactivation by TIF1ß via Tau-1 seems additive rather than cooperative with the AR coactivation by TIF2. Some mutations naturally occurring in androgen-insensitivity syndrome patients that reside in Tau-1 seem to impair the TIF1ß coactivation of the AR, indicating that TIF1ß could also be relevant for the in vivo androgen response in humans. Moreover, since TIF1ß is well expressed in prostate cancer cells, its functional interaction with androgen signalling could in the long run be a therapeutic target for this disease.
Subject(s)
Receptors, Androgen/metabolism , Repressor Proteins/physiology , Cell Line , HEK293 Cells , HeLa Cells , Humans , Male , Nuclear Receptor Coactivator 2/physiology , Prostate/metabolism , Receptors, Androgen/genetics , Repressor Proteins/genetics , Transcriptional Activation , Tripartite Motif-Containing Protein 28ABSTRACT
A cytogenetic analysis of primitive neuroectodermal tumor (PNET) cell lines was undertaken. PNET are presumed to be embryologically related to, but clinically and histologically distinct from, other tumors of neuroectodermal origin, including neuroblastoma and retinoblastoma. No single chromosome abnormality was found in all five of the tumors studied. In three of the five cases, however, additional 1q material [either as extra chromosome #1 or i(1q)] was found in all cells, and in two of the five, monosomy 13 was noted in all cells; the possible significance of these findings is discussed.
