TRPS1 Suppresses Breast Cancer Epithelial-mesenchymal Transition Program as a Negative Regulator of SUZ12

Breast cancer (BC) is among the most common malignant diseases and metastasis is the handcuff of treatment. Cancer metastasis is a multistep process associated with the epithelial-mesenchymal transition (EMT) program. Several studies have demonstrated that transcriptional repressor GATA binding 1 (TRPS1) played important roles in development and progression of primary BC. In this study we sought to identify the mechanisms responsible for this function of TRPS1 in the continuum of the metastatic cascade. Here we described that TRPS1 was significantly associated with BC metastasis using public assessable datasets. Clinically, loss of TRPS1 expression in BC was related to higher histological grade. In vitro functional study and bioinformatics analysis revealed that TRPS1 inhibited cell migration and EMT in BC. Importantly, we identified SUZ12 as a novel target of TRPS1 related to EMT program. ChIP assay demonstrated TRPS1 directly inhibited SUZ12 transcription by binding to the SUZ12 promoter. Loss of TRPS1 resulted in increased SUZ12 binding and H3K27 tri-methylation at the CDH1 promoter and repression of E-cadherin. In all, our data indicated that TRPS1 maintained the expression of E-cadherin by inhibiting SUZ12, which might provide novel insight into how loss of TRPS1 contributed to BC progression

IDH1R132H Promotes Malignant Transformation of Benign Prostatic Epithelium by Dysregulating MicroRNAs: Involvement of IGF1R-AKT/STAT3 Signaling Pathway

Risk stratification using molecular features could potentially help distinguish indolent from aggressive prostate cancer (PCa). Mutations in isocitrate dehydrogenase (IDH) acquire an abnormal enzymatic activity, resulting in the production of 2-hydroxyglutarate and alterations in cellular metabolism, histone modification, and DNA methylation. Mutant IDH1 has been identified in various human malignancies, and IDH1R132H constituted the vast majority of mutational events of IDH1. Most recent studies suggested that IDH1 mutations define a methylator subtype in PCa. However, the function of IDH1R132H in PCa development and progression is largely unknown. In this study, we showed that the prevalence of IDH1R132H in Chinese PCa patients is 0.6% (2/336). Of note, IDH1R132H-mutant PCa patients lacked other canonical genomic lesions (e.g., ERG rearrangement, PTEN deletion) that are common in most other PCa patients. The in vitro experiment suggested that IDH1R132H can promote proliferation of benign prostate epithelial cell RWPE-1 when under the situation of low cytokine. It could also promote migration capacity of RWPE-1 cells. Mechanistically, IDH1R132H was an important regulator of insulin-like growth factor 1receptor (IGF1R) by downregulating a set of microRNAs (miR-141-3p, miR-7-5p, miR-223-3p). These microRNAs were repressed by the alteration of epigenetic modification to decrease the enrichment of active marker H3K4me3 or to increase repressive marker H3K27me3 at their promoters. Collectively, we proposed a novel model for an IDH1R132H-microRNAs-IGF1R regulatory axis, which might provide insight into the function of IDH1R132H in PCa development