NFATc1 promotes prostate tumorigenesis and overcomes PTEN loss-induced senescence

Abstract

Despite recent insights into prostate cancer (PCa)-associated genetic changes, full understanding of prostate tumorigenesis remains elusive due to complexity of interactions among various cell types and soluble factors present in prostate tissue. We found upregulation of Nuclear Factor of Activated T Cells c1 (NFATc1) in human PCa and cultured PCa cells, but not in normal prostates and non-tumorigenic prostate cells. To understand the role of NFATc1 in prostate tumorigenesis in situ, we temporally and spatially controlled the activation of NFATc1 in mouse prostate and showed that such activation resulted in prostatic adenocarcinoma with features similar to those seen in human PCa. Our results indicate that the activation of a single transcription factor, NFATc1 in prostatic luminal epithelium to PCa can affect expression of diverse factors in both cells harboring the genetic changes and in neighboring cells through microenvironmental alterations. In addition to the activation of oncogenes c-MYC and STAT3 in tumor cells, a number of cytokines and growth factors, such as IL1β, IL6, and SPP1 (Osteopontin, a key biomarker for PCa), were upregulated in NFATc1-induced PCa, establishing a tumorigenic microenvironment involving both NFATc1 positive and negative cells for prostate tumorigenesis. To further characterize interactions between genes involved in prostate tumorigenesis, we generated mice with both NFATc1 activation and Pten inactivation in prostate. We showed that NFATc1 activation led to acceleration of Pten-null–driven prostate tumorigenesis by overcoming the PTEN loss–induced cellular senescence through inhibition of p21 activation. This study provides direct in vivo evidence of an oncogenic role of NFATc1 in prostate tumorigenesis and reveals multiple functions of NFATc1 in activating oncogenes, in inducing proinflammatory cytokines, in oncogene addiction, and in overcoming cellular senescence, which suggests calcineurin-NFAT signaling as a potential target in preventing PCa.

Dynamics of the cell-free DNA methylome of metastatic prostate cancer during androgen-targeting treatment

“…In most cases, regardless of visit comparison, the methylation pattern for these genes clustered closely for the same patients. One such group of genes with increases in methylation at Visit C included NFATC1 , which can promote tumorigenesis (44), and a histone deacetylase, HDAC4 . While several Enzalutamide-specific genes were found ( Supplementary table 3 ), common pathways including several differentiation-related and neuronal pathways were found among gene-body associated DMRs ( Supplementary Figures 11 & 12 ),…”

“…Commonly altered genes in the promoter region included PYCR1 and SHARPIN, which are known to be upregulated in PCa tissue and involved in processes such as proliferation and angiogenesis (55). Gene body methylation changes were observed in genes that regulate various tumorigenic processes, including NFATC1 (47) , PRDM16 (56), and OPCML (57). Pathway analysis also further highlighted key mechanisms that have been established in prostate tumor tissue studies, including the wnt pathway (16).…”

Regulator of Calcineurin 1 Gene Isoform 4, Down-regulated in Hepatocellular Carcinoma, Prevents Proliferation, Migration, and Invasive Activity of Cancer Cells and Metastasis of Orthotopic Tumors by Inhibiting Nuclear Translocation of NFAT1

“…17 Several key findings have pointed to important roles of calcineurin-NFAT signaling in modulating phenotypes associated with malignancy and tumor progression. [32][33][34] Recently, the implication of NFAT1 in oncogenic processes has begun to be understood. NFAT1 and its upstream activator calcineurin are essential to the tumorigenic and metastatic properties of breast cancer cells.…”

The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

“…Intracellular calcium levels have been shown to increase in various cell types in response to senescence‐inducing stresses (Borodkina et al, 2016; Wiel et al, 2014; Yu, Li, et al, 2013; Yu, Zhang, Zhou, Yao, & Li, 2013) and activation of the calcium‐dependent transcription factor nuclear factor of activated T cells (NFAT) by the calcium/calmodulin/calcineurin pathway is known to regulate senescence (Manda et al, 2016; Wu et al, 2010). However, how calcium signaling is controlled is still only partially understood.…”