PRMT1 potentiates chondrosarcoma development through activation of YAP activity

Abstract

Protein arginine methyltransferase 1 (PRMT1) is identified as an oncogene implicated in various types of human cancers, while Yes‐associated protein (YAP) as a key transcriptional coactivator of the Hippo signaling plays a vital role in tissue homeostasis and tumorigenesis. To date, the underlying biological functions, prognostic values, and potential mechanisms of PRMT1 and YAP in chondrosarcoma development have not been clearly elucidated. Here, we show that upregulation of PRMT1 and YAP is significantly detected in human chondrosarcoma specimens. Elevated levels of PRMT1 positively correlated with YAP nuclear accumulation are significantly associated with high‐grade chondrosarcoma and poor prognosis. Moreover, YAP is recognized as an independent prognostic factor for chondrosarcoma patients. Ectopic expression of PRMT1 potentiates, but depletion of PRMT1 attenuates, chondrosarcoma cell growth in vitro and in vivo. Mechanistically, we have discovered that PRMT1 functions upstream of LATS1 and suppresses LATS1‐mediated phosphorylation of YAP (Ser127), and thus promotes chondrosarcoma cell survival in a YAP‐dependent manner. Collectively, our study identifies PRMT1 as a positive regulator of YAP activity in chondrosarcoma, highlighting a novel therapeutic target against chondrosarcoma and other YAP‐driven cancers.

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

“…Although YAP/TAZ were not investigated in these studies, it may be speculated that the observed molecular alterations affected chondrosarcoma adherence and invasion phenotypes through abrogated YAP/TAZ signaling. A recent study identified YAP nuclear accumulation as a consequence of LATS1 inactivation by protein arginine methyltransferase 1 (PRMT1) as an independent bad prognostic factor in chondrosarcoma [181]. Finally, the treatment of chondrosarcoma cells with the BET-bromodomain inhibitor JQ1 downregulated YAP/TAZ and LATS1, leading to the upregulation of cyclin-dependent kinase inhibitor 1a (CDKN1A/p21) and cell cycle arrest, senescence and apoptosis [182].…”

Dysregulation of Zinc Finger Protein 395 Contributes to the Pathogenesis of Chondrosarcoma

“… 19 Clinical clinicopathological information and follow-up data were reported previously, and signed informed consent for sample collection and analysis were obtained from all patients and was in full compliance with national legislation and the ethical standards as described previously (IRB00001052-08044). 20 , 21 Human chondrosarcoma SW1353 cell line was purchased from the American Type Culture Collection (Bethesda, MD, USA) and maintained in Dulbecco’s modified Eagle medium (DMEM, Gibco, Grand Island, NY, USA) containing 10% fetal bovine serum (FBS, Gibco) and cultured in a humidified cell incubator with 5% CO 2 at 37°C.…”

“…Detailed experimental protocols have been described previously. 19 , 20 Typically, after antigen retrieval, ZNF395 (Proteintech, 13149-1-AP; 1:100) immunoreactivities were detected using the EnVision+, Peroxidase system (DAKO Diagnostics, Denmark). The slides were incubated with DAB substrate (DAKO Diagnostics, Denmark) and counterstained with hematoxylin.…”

“…Cell Counting Kit-8 (Dojindo, Kumamoto, Japan) for cell viability, and clonogenic formation assays were conducted as described previously. 20 , 23 Briefly, SW1353 cells were seeded into 96-well plates at 5000 cells per well for 24 hours and assessed using CCK-8 at the indicated time. For clonogenic assay, after treatment, the number of viable cell colonies was determined after either 10 days SW1353 cells post inoculation of 150 cells per well in triplicate in 12-well plates.…”

“…Colonies were counted after methanol/acetone (1:1) fixation and Gentian Violet staining according to the previous experimental protocols. 20 …”