Stabilization of ADAM9 by N-α-acetyltransferase 10 protein contributes to promoting progression of androgen-independent prostate cancer

Abstract

N-α-Acetyltransferase 10 protein (Naa10p) was reported to be an oncoprotein in androgen-dependent prostate cancer (PCa; ADPC) through binding and increasing transcriptional activity of the androgen receptor (AR). PCa usually progresses from an androgen-dependent to an androgen-independent stage, leading to an increase in the metastatic potential and an incurable malignancy. At present, the role of Naa10p in androgen-independent prostate cancer (AIPC) remains unclear. In this study, in silico and immunohistochemistry analyses showed that Naa10 transcripts or the Naa10p protein were more highly expressed in primary and metastatic PCa cancer tissues compared to adjacent normal tissues and non-metastatic cancer tissues, respectively. Knockdown and overexpression of Naa10p in AIPC cells (DU145 and PC-3M), respectively, led to decreased and increased cell clonogenic and invasive abilities in vitro as well as tumor growth and metastasis in AIPC xenografts. From the protease array screening, we identified a disintegrin and metalloprotease 9 (ADAM9) as a potential target of Naa10p, which was responsible for the Naa10p-induced invasion of AIPC cells. Naa10p can form a complex with ADAM9 to maintain ADAM9 protein stability and promote AIPC’s invasive ability which were independent of its acetyltransferase activity. In contrast to the Naa10p-ADAM9 axis, ADAM9 exerted positive feedback regulation on Naa10p to modulate progression of AIPC in vitro and in vivo. Taken together, for the first time, our results reveal a novel cross-talk between Naa10p and ADAM9 in regulating the progression of AIPC. Disruption of Naa10p–ADAM9 interactions may be a potential intervention for AIPC therapy.

Ubiquitin‐specific peptidase 39 promotes human glioma cells migration and invasion by facilitating ADAM9 mRNA maturation

“…ADAM9 owns shedding and adhesive properties depending on its metalloproteinase and disintegrin domains, respectively [20]. Increased ADAM9 expression has been reported in various cancers, such as hepatocellular carcinoma [21], prostate cancer [22], breast cancer [23,24], non‐small cell lung cancer [25], skin melanoma [26] and glioma [27]. It was reported that the mRNA levels of ADAM9 were positively associated with histological type and tumor grade in human glioma and could act as a prognostic factor in patients with lower‐grade glioma [27].…”

The ADAM9/WISP-1 axis cooperates with osteoblasts to stimulate primary prostate tumor growth and metastasis

“…In triple-negative breast cancer (TNBC), higher ADAM9 expression correlates significantly with poorer outcomes, while inhibition of ADAM9 expression lowers TNBC cell aggressiveness by suppressing AKT/NF-κB signaling 38 . In androgen-independent PCa, ADAM9 can form a complex with N -α-acetyltransferase 10 protein to maintain ADAM9 protein stability and thus promote tumor cell invasiveness and in vivo tumor progression 39 . ADAM9 also serves as a significant and independent prognostic marker associated with prostate-specific antigen relapse-free survival in PCa patients treated with ADT 40 .…”

Naa10p promotes cell invasiveness of esophageal cancer by coordinating the c-Myc and PAI1 regulatory axis

“…Myosin light chain kinase (MLCK), which plays a central role in controlling actin-myosin interaction, was found to be acetylated and suppressed by Naa10p and thus resulted in decreased cell migration [ 42 ]. In contrast, Naa10p can form a complex with ADAM9 to promote cell invasiveness of androgen-independent prostate cancer [ 43 ]. We have recently identified MMP-2 as an N-terminal acetyltransferase substrate of Naa10p in osteosarcoma.…”