Unravelling the Role of P300 and TMPRSS2 in Prostate Cancer: A Literature Review

Abstract

Prostate cancer is one of the most common malignant diseases in men, and it contributes significantly to the increased mortality rate in men worldwide. This study aimed to review the roles of p300 and TMPRSS2 (transmembrane protease, serine 2) in the AR (androgen receptor) pathway as they are closely related to the development and progression of prostate cancer. This paper represents a library-based study conducted by selecting the most suitable, up-to-date scientific published articles from online journals. We focused on articles that use similar techniques, particularly those that use prostate cancer cell lines and immunohistochemical staining to study the molecular impact of p300 and TMPRSS2 in prostate cancer specimens. The TMPRSS2:ERG fusion is considered relevant to prostate cancer, but its association with the development and progression as well as its clinical significance have not been fully elucidated. On the other hand, high p300 levels in prostate cancer biopsies predict larger tumor volumes, extraprostatic extension of disease, and seminal vesicle involvement at prostatectomy, and may be associated with prostate cancer progression after surgery. The inhibition of p300 has been shown to reduce the proliferation of prostate cancer cells with TMPRSS2:ETS (E26 transformation-specific) fusions, and combining p300 inhibitors with other targeted therapies may increase their efficacy. Overall, the interplay between the p300 and TMPRSS2 pathways is an active area of research.

Keywords: Gleason score; TMPRSS2; androgen receptor; molecular pathology; p300; precision medicine; prostate cancer.

Figure 1

AR pathway in hormone-dependent prostate cancer cells. Under normal physiological conditions, the synthesis of androgens takes place in the Leydig cells of the testicles and in the zona reticularis of the adrenal gland. Testosterone, the prototypical androgenic steroid hormone, circulates in the bloodstream, bound to sex hormone-binding globulin (SHBG) or as free testosterone. Upon reaching the prostate cell, testosterone dissociates from SHBG and transverses the cellular membrane via diffusion. The enzymatic conversion of testosterone to DHT is mediated by 5a-reductase. Following binding with DHT, the androgen receptor (AR) dissociates from the heat shock protein (HSP). The DHT-AR complex undergoes conformational changes and is translocated within the nucleus, where it dimerizes. p300 acts as histone acetyltransferase (HAT) promoting the formation of euchromatin, which facilitates the binding of the DHT-AR dimer to the androgen-responsive elements (ARE) in the promoter region of the TMPRSS2 gene. In addition, p300 functions as a co-activator, enhancing gene transcription and resulting in the overexpression of the ERG oncogene. Created with BioRender.com. (Created on 30 March 2023).