Abstract
Recent studies have demonstrated that the androgen receptor (AR) could play important roles to promote renal cell carcinoma (RCC) cell proliferation, and other studies have also indicated that suppressing the argininosuccinate synthase 1 (ASS1) could promote proliferation of various tumors. The potential of AR promoting cell proliferation in RCC via altering ASS1, however, remains unclear. Here we found that the expression of ASS1 was lower in RCC tissues than in adjacent normal renal tissues, and a lower ASS1 expression was linked to a worse prognosis in RCC patients. Mechanism dissection showed that AR could decrease ASS1 expression to promote RCC cell proliferation via ASS1P3, a pseudogene of ASS1. The results of RIP assay and AGO2 assay revealed that AR could bind ASS1P3 to increase RCC cell proliferation via altering miR-34a-5p function, which could bind to the 3′UTR of ASS1 to suppress its protein expression. ASS1P3 could function as a miRNA decoy for miR-34a-5p to regulate ASS1 in RCC. Preclinical study also supports the in vitro data. Together, these results demonstrated that ASS1P3 could function as a competing endogenous RNA to suppress RCC cell progression, and targeting this newly identified AR-mediated ASS1P3/miR-34a-5p/ASS1 signaling might help in blocking proliferation.
Highlights
Siegel et al reported that renal cell carcinoma (RCC)would account for ~3.77% of new adult malignancies in the United States in 20181
Mechanism dissection of why androgen receptor (AR) can increase RCC cell proliferation: by suppressing argininosuccinate synthase 1 (ASS1) expression To dissect the mechanisms underlying AR’s promotion of RCC cell proliferation, we focused on the ASS1, as recent studies have indicated that decreased ASS1 activity might lead to an increase in the tumor growth[6,7]
We found that ASS1 had 12 pseudogenes that had similar functions with long noncoding RNAs (lncRNAs) and could regulate their cognate genes as competing endogenous RNAs (ceRNAs) by competing with miRNAs
Summary
Siegel et al reported that renal cell carcinoma (RCC)would account for ~3.77% of new adult malignancies in the United States in 20181. The incidence of RCC is 45.13% and it has a high death rate due to its rapid progression and late diagnosis[1]. Extensive studies indicate RCC like all other human tumors is the result of misregulation at multiple levels, including noncoding RNAs (ncRNAs), epigenetic regulation, or posttranslational modifications. Epidemiology studies indicate there is a gender difference in the incidence of RCC with a male:female ratio of 1.88:1.01, suggesting that sex hormones and/or their receptors may play important roles in the development of RCC. Arginine is an important amino acid especially for the young, which plays key roles in many metabolic pathways, such as the production of urea, nitric oxide, and proline[4,5]. A loss of ASS1 expression has been found in many tumors, Official journal of the Cell Death Differentiation Association
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