Knockdown of Mediator Complex Subunit 19 Suppresses the Growth and Invasion of Prostate Cancer Cells

Abstract

Prostate cancer (PCa) is one of the most common cancers in elderly men. Mediator Complex Subunit 19 (Med19) is overexpressed and plays promotional roles in many cancers. However, the roles of Med19 in PCa are still obscure. In this study, by using immunohistochemical staining, we found higher expression level of Med19 in PCa tissues than in adjacent benign prostate tissues. We then knocked down the Med19 expression in PCa cell lines LNCaP and PC3 by using lentivirus siRNA. Cell proliferation, anchor-independent growth, migration, and invasion were suppressed in Med19 knockdown PCa cells. In nude mice xenograft model, we found that Med19 knockdown PCa cells formed smaller tumors with lower proliferation index than did control cells. In the mechanism study, we found that Med19 could regulate genes involved in cell proliferation, cell cycle, and epithelial-mesenchymal transition, including P27, pAKT, pPI3K, IGF1R, E-Cadherin, N-Cadherin, Vimentin, ZEB2, Snail-1 and Snail-2. Targeting Med19 in PCa cells could inhibit the PCa growth and metastasis, and might be a therapeutic option for PCa in the future.

The mediator complex in genomic and non-genomic signaling in cancer

“…Beyond its interaction with ER, MED1 was shown to be essential for the expression of ER target genes and proliferation in breast cancer cells [15, 50]. In line with other studies on the dispensability of MED1, MED1 was only present in about 20% of mediator complexes, with MED1-containing Mediator also enriched for MED19 and MED15, both of which have been implicated in breast cancer, as well as prostate cancer (discussed below) [15, 20, 38, 51, 52]. This indicates that MED19 and MED15 may cooperate with MED1 in breast cancer to promote ER activity.…”

“…Indeed, depletion of MED19 by siRNA reduced the expression of AR target genes in LNCaP-abl cells (androgen-independent prostate cancer cell line), and reduced the proliferation in both LNCaP-abl cells and LNCaP cells (androgen-dependent prostate cancer cell line) [20]. MED19 has also been implicated in the growth of prostate cancer cells in other studies [37, 38]. Although no studies have examined MED19 as an ER co-regulator, it has been demonstrated to play a role in the growth of breast cancer cells, indicating that it may regulate ER signaling [39, 40].…”

“…Alteration of MED19 mRNA, which was upregulated in a subset of prostate cancer patients, correlated with poor outcome [20]. A later study demonstrated overexpression of MED19 protein in primary prostate tumor compared to benign tissue [38]. Depletion of MED19 in LNCaP cells reduced proliferation, invasion, and xenograft growth, and it was suggested that MED19 may promote tumor growth and metastasis through the regulation of expression of pro-apoptotic, cell cycle, and EMT genes, such as Bid, p27, and N-cadherin [37, 38].…”

“…A later study demonstrated overexpression of MED19 protein in primary prostate tumor compared to benign tissue [38]. Depletion of MED19 in LNCaP cells reduced proliferation, invasion, and xenograft growth, and it was suggested that MED19 may promote tumor growth and metastasis through the regulation of expression of pro-apoptotic, cell cycle, and EMT genes, such as Bid, p27, and N-cadherin [37, 38]. However, the mechanism by which MED19 regulates these genes, the specific signaling pathways it activates in prostate cancer, and how this intersects with its role as an AR co-regulator, have yet to be elucidated.…”

<p>The SP1-Induced Long Noncoding RNA, LINC00339, Promotes Tumorigenesis in Colorectal Cancer via the miR-378a-3p/MED19 Axis</p>

“…29 MED19 downregulation inhibited colony formation, migration, and invasion, as well as cell growth and EMT-related genes such as p27, E-Cadherin, N-Cadherin, vimentin, snail-1 and snail-2 in prostate cancer. 30 Interfering with MED19 induced cell cycle arrest at the G1 phase and prohibited migration in tongue cancer cells. 31 Here, we revealed that MED19 induced the EMT process by activating the Wnt/βcatenin pathway in CRC, providing a possible mechanism by which MED19 affects tumorigenesis and metastasis.…”