Nuclear PRMT1 expression is associated with poor prognosis and chemosensitivity in gastric cancer patients

Abstract

Background Metastatic and refractory gastric cancer (GC) are associated with a poor prognosis; therefore, the identification of prognostic factors and chemosensitivity markers is extremely important. Protein arginine methyltransferase 1 (PRMT1) may play a role in chemosensitivity/apoptosis induction via activation of the tumor suppressor forkhead box O1 (FOXO1). The purpose of this study was to clarify the expression of and relationship between PRMT1 and FOXO1 to evaluate the applicability of PRMT1 as a prognostic marker and a therapeutic tool in GC. Methods We investigated the clinical and functional significance of PRMT1 and FOXO1 in 195 clinical GC samples using immunohistochemistry. We performed suppression analysis of PRMT1 using small interfering RNA to determine the biological roles of PRMT1 in chemosensitivity. Results PRMT1 and FOXO1 in GC samples were predominantly expressed in the nucleus. Patients with lower PRMT1 expression (n = 131) had suppressed nuclear accumulation of FOXO1, higher recurrence after adjuvant chemotherapy, and poorer prognosis than those with higher PRMT1 expression (n = 64). PRMT1 downregulation in GC cells by RNA interference inhibited cisplatin and 5-fluorouracil sensitivity. The expression of phosphorylated FOXO1 and phosphorylated BCL-2 antagonist of cell death was upregulated in PRMT1 small interfering RNA groups. Conclusion Our data suggest that the evaluation of PRMT1 expression in GC is a useful predictor of poor prognosis and recurrence after adjuvant chemotherapy. Moreover, these data suggest that PRMT1 is a promising therapeutic tool for overcoming refractory GC.

PRMT1 potentiates chondrosarcoma development through activation of YAP activity

“…Similarly, YAP is also elevated in various cancers, and emerges as an oncoprotein increasingly being recognized as a promising therapeutic target . Previous studies had documented that overexpression of PRMT1 led to the progression and metastasis of various cancers and predicted a worse prognosis in tumor patients . In addition, nuclear YAP accumulation was independently predictive of poor prognosis in .…”

“…Previous studies have documented that PRMT1 and YAP can be predictive for the prognosis of patients with several solid tumors, [10][11][12]24,25 thus we had conducted the Kaplan-Meier analysis, and showed that the overall survival rate of patients with high PRMT1 level and YAP-positive tumors was significantly lower than that of patients with low PRMT1 level and YAP-negative tumors, respectively (P = .001; Figure 1G and 1H). Moreover, the combination of PRMT1 level and YAP accumulation had a significant impact on the overall survival (P = .001; Figure 1I).…”

“…The slides were developed with DAB (diaminobenzidine) substrate (DAKO Diagnostics) and counterstained with hematoxylin. PRMT1 staining was evaluated using the following criteria as described previously and modified: nuclear immunoreactivity of PRMT1 was assessed as follows: (a) a low expression level group, defined as scores of 0 for no staining and 1+ for weak staining; and (b) a high expression level group, defined as a score of 2+ for moderate staining and 3+ for strong staining. In particular, immunopositive scoring results for YAP nuclear accumulation were available as reported previously and modified .…”

“…PRMT1 is the predominant type I PRMTs in mammalian cells, responsible for at least 85% of all arginine methylation reactions in human cells, and has been involved in various types of human cancers . Overexpression of PRMT1 is markedly correlated with disease progression and poor prognosis of the lung, gastric, and colon cancer . Ectopic expression of PRMT1 is associated with the induction of proliferation and inhibition of apoptosis in lung cancer and gliomas .…”

“…9 Overexpression of PRMT1 is markedly correlated with disease progression and poor prognosis of the lung, gastric, and colon cancer. [10][11][12] Ectopic expression of PRMT1 is associated with the induction of proliferation and inhibition of apoptosis in lung cancer and gliomas. 10,13 Conversely, blockade of PRMT1 is reported to suppress the proliferation potency of bladder and lung cancer cells, 14 and enhances chemosensitivity via inhibition of DNA repair in osteosarcoma cells, 15 and also induces the suppression of cancer cell growth and metastasis.…”