DNMT3A/miR-129-2-5p/Rac1 Is an Effector Pathway for SNHG1 to Drive Stem-Cell-like and Invasive Behaviors of Advanced Bladder Cancer Cells

Abstract

The stem-cell-like behavior of cancer cells plays a central role in tumor heterogeneity and invasion and correlates closely with drug resistance and unfavorable clinical outcomes. However, the molecular underpinnings of cancer cell stemness remain incompletely defined. Here, we show that SNHG1, a long non-coding RNA that is over-expressed in ~95% of human muscle-invasive bladder cancers (MIBCs), induces stem-cell-like sphere formation and the invasion of cultured bladder cancer cells by upregulating Rho GTPase, Rac1. We further show that SNHG1 binds to DNA methylation transferase 3A protein (DNMT3A), and tethers DNMT3A to the promoter of miR-129-2, thus hyper-methylating and repressing miR-129-2-5p transcription. The reduced binding of miR-129-2 to the 3′-UTR of Rac1 mRNA leads to the stabilization of Rac1 mRNA and increased levels of Rac1 protein, which then stimulates MIBC cell sphere formation and invasion. Analysis of the Human Protein Atlas shows that a high expression of Rac1 is strongly associated with poor survival in patients with MIBC. Our data strongly suggest that the SNHG1/DNMT3A/miR-129-2-5p/Rac1 effector pathway drives stem-cell-like and invasive behaviors in MIBC, a deadly form of bladder cancer. Targeting this pathway, alone or in combination with platinum-based therapy, may reduce chemoresistance and improve longer-term outcomes in MIBC patients.

The Diagnostic and Therapeutic Role of snoRNA and lincRNA in Bladder Cancer

“…The latest studies on the functions and mechanisms of SNHGs in BLCA are described below (Table 1). SNHG1, which is located at chromosome 11q12.3, is overexpressed in several types of tumours, including pancreatic, prostate, non-small-cell lung and BLCA [21][22][23][24]. It is widely considered an oncogene that promotes cancer proliferation, migration, invasion and tumorigenesis.…”

“…A recent study revealed that elevated SNHG1 could interact with the DNA methyltransferase DNMT3A and then bind to and hypermethylate the promoter of miR-129-5p. The low expression of miR-129-5p maintains the stability of Rac1 mRNA, resulting in increased stemness and invasiveness of BLCA cells [22]. Moreover, SNHG1 upregulates the histone methyltransferase EZH2 by direct interaction and functions as a sponge of miR-137-3p.…”