EZH2-TROAP Pathway Promotes Prostate Cancer Progression Via TWIST Signals

Abstract

Trophinin-associated protein (TROAP) has been shown to be overexpressed and promotes tumor progression in some tumors. We performed this study to assess the biological and clinical significance of TROAP in prostate cancer. We downloaded TROAP mRNA expression data from TCGA and GEO databases. We analyzed expressions of TROAP and other genes in prostate cancer tumors at different stages and assessed Gleason scores. We used Celigo image, Transwell, and rescue assays, and flow cytometry detection to assess growth, apoptosis, proliferation, migration, and invasion of the prostate cancer cells. We identified and validated up- and down-stream genes in the TROAP pathway. The mRNA data suggested that TROAP expression was markedly upregulated in prostate cancer compared with its expression in normal tissues, especially in cancers with high stages and Gleason scores. Moreover, a high TROAP expression was associated with poor patient survival. Results of our in vitro assay showed that TROAP knockdown inhibited DU145 and PC3 cell proliferation and viability via cell apoptosis and S phase cycle arrest. The Transwell assay showed that TROAP knockdown inhibited cell migration and invasion, probably through MMP-9 and E-Cadherin modulation. Overexpression of TWIST partially abrogated the inhibitory effects of TROAP knockdown on prostate cancer cells. Our integrative mechanism dissection revealed that TROAP is in a pathway downstream of EZH2 and that it activates the TWIST/c-Myc pathway to regulate prostate cancer progression. In all, we identified TROAP as a driver of prostate cancer development and progression, providing a novel target for prostate cancer treatments.

Suppression of CDCA3 inhibits prostate cancer progression via NF‑κB/cyclin D1 signaling inactivation and p21 accumulation

“…Prostate cancer is the most common type of malignant tumor in males and is the leading cause of cancer-related mortality in numerous countries (1,2). At present, in 2021 there have been ~248,530 new cases and 34,130 deaths as a result of prostate cancer in the United States alone (3).…”

The long and short non-coding RNAs modulating EZH2 signaling in cancer

“…Prostate cancer is a common tumor among men and EZH2 has been shown to play a role in its malignancy affecting growth and senescence [ 187 ]. Furthermore, EZH2 can enhance prostate cancer metastasis via Twist upregulation and increasing N-cadherin levels [ 188 ]. The expression of miRNA-605-3p as a tumor-suppressor factor is down-regulated in prostate cancer cells, which increases the expression of EZH2 to disrupt prostate cancer growth and metastasis.…”

Identification of Biomarkers and Trajectories of Prostate Cancer Progression: A Bioinformatics Fusion of Weighted Correlation Network Analysis and Machine Learning

“…The trajectory was characterized by a gradual up-regulation of genes such as EZH2 and TROAP highlighting the central role of these two genes for PCa progression. Interestingly, TROAP was shown to be downstream of EZH2 and is important for PCa progression via the TWIST/c-MYC pathway (Jin et al , 2021). EZH2 is currently assessed as a therapeutic target for mCRPC in clinical studies, using the EZH2 inhibitor tazemetostat in combination with androgen signaling inhibitors (NCT04179864) or the PARPi talazoparib (NCT04846478).…”