The AR/NCOA1 axis regulates prostate cancer migration by involvement of PRKD1

Abstract

Due to the urgent need for new prostate cancer (PCa) therapies, the role of androgen receptor (AR)-interacting proteins should be investigated. In this study we aimed to address whether the AR coactivator nuclear receptor coactivator 1 (NCOA1) is involved in PCa progression. Therefore, we tested the effect of long-term NCOA1 knockdown on processes relevant to metastasis formation. [ 3 H]-thymidine incorporation assays revealed a reduced proliferation rate in AR-positive MDA PCa 2b and LNCaP cells upon knockdown of NCOA1, whereas AR-negative PC3 cells were not affected. Furthermore, Boyden chamber assays showed a strong decrease in migration and invasion upon NCOA1 knockdown, independently of the cell line's AR status. In order to understand the mechanistic reasons for these changes, transcriptome analysis using cDNA microarrays was performed. Protein kinase D1 (PRKD1) was found to be prominently up-regulated by NCOA1 knockdown in MDA PCa 2b, but not in PC3 cells. Inhibition of PRKD1 reverted the reduced migratory potential caused by NCOA1 knockdown. Furthermore, PRKD1 was negatively regulated by AR. Immunohistochemical staining of PCa patient samples revealed a strong increase in NCOA1 expression in primary tumors compared with normal prostate tissue, while no final conclusion could be drawn for PRKD1 expression in tumor specimens. Thus, our findings directly associate the AR/NCOA1 complex with PRKD1 regulation and cellular migration and support the concept of therapeutic inhibition of NCOA1 in PCa.

The oncogenic roles of nuclear receptor coactivator 1 in human esophageal carcinoma

“…NCOA1 overexpression has been demonstrated in multiple cancers. 47,[51][52][53][54][55] The elevated levels of NCOA1 mRNA and increased gene copy number of NCOA1 found in this research suggest that both gene amplification and increased transcription could be part of the underlying mechanisms of NCOA1 overexpression in human ESCC. In addition, Cox analysis showed that the protein levels of NCOA1 are inversely proportional to ESCC patient survival.…”

Non‐coding and coding genomic variants distinguish prostate cancer, castration‐resistant prostate cancer, familial prostate cancer, and metastatic castration‐resistant prostate cancer from each other

“…PPARGC1A is a transcriptional coactivator that regulates the genes involved in energy metabolism and is associated with aggressive prostate cancer . NCOA1 is a transcriptional coactivator for steroid and nuclear hormone receptors where the AR/NCOA1 axis regulates prostate cancer migration by involvement of PRKD1 …”

“…49 NCOA1 is a transcriptional coactivator for steroid and nuclear hormone receptors where the AR/NCOA1 axis regulates prostate cancer migration by involvement of PRKD1. 50 Many intronic variants were found on LGALS8, ABL2, PDE4B, and IL6R (Supporting Information 2). It has been reported that microRNA-20a promotes invasive prostate cancer by targeting ABL2.…”

High expression of miR-105-1 positively correlates with clinical prognosis of hepatocellular carcinoma by targeting oncogene NCOA1

“…Moreover, NCOA1 could promote angiogenesis in breast tumors by simultaneously enhancing both HIF1α- and AP-1-mediated VEGF-a transcription [31]. NCOA1, as the androgen receptor (AR) coactivator, was found to be involved in prostate cancer progression, while NCOA1 knockdown induced a significant decrease in migration and invasion through the upregulation of protein kinase D1 (PRKD1) [32]. Besides, NCOA1 expression was shown to have prognostic significance in advanced-stage head and neck carcinoma [33].…”