A regulatory network comprising let-7 miRNA and SMUG1 is associated with good prognosis in ER+ breast tumours

Abstract

Single-strand selective uracil–DNA glycosylase 1 (SMUG1) initiates base excision repair (BER) of uracil and oxidized pyrimidines. SMUG1 status has been associated with cancer risk and therapeutic response in breast carcinomas and other cancer types. However, SMUG1 is a multifunctional protein involved, not only, in BER but also in RNA quality control, and its function in cancer cells is unclear. Here we identify several novel SMUG1 interaction partners that functions in many biological processes relevant for cancer development and treatment response. Based on this, we hypothesized that the dominating function of SMUG1 in cancer might be ascribed to functions other than BER. We define a bad prognosis signature for SMUG1 by mapping out the SMUG1 interaction network and found that high expression of genes in the bad prognosis network correlated with lower survival probability in ER+ breast cancer. Interestingly, we identified hsa-let-7b-5p microRNA as an upstream regulator of the SMUG1 interactome. Expression of SMUG1 and hsa-let-7b-5p were negatively correlated in breast cancer and we found an inhibitory auto-regulatory loop between SMUG1 and hsa-let-7b-5p in the MCF7 breast cancer cells. We conclude that SMUG1 functions in a gene regulatory network that influence the survival and treatment response in several cancers.

Construction of ceRNA prognostic model based on the CCR7/CCL19 chemokine axis as a biomarker in breast cancer

“…most of the miRNAs in the Let-7 family, except let-7a-3, are oncogenes, which are involved in oncocyte cycle regulation and affect cancer cell migration and invasion. Numerous studies have shown that hsa-let-7b-5p functions as a tumor suppressor in cervical cancer, breast cancer and glioma [ 34 , 35 ].RiskScore combines clinical factors (age and stage) to further diagnose the survival risk of BC patients for clinicians. Some studies reported [ 36 ] that TNM stage and tumor size differed in metastatic and non-metastatic BC ( P < 0.001), suggesting that our model may be a good predictor of tumor metastasis.…”

DNA Glycosylases Define the Outcome of Endogenous Base Modifications

“…SMUG1 knockdown leads to the accumulation of 5-hydroxymethyluridine in RNA, accompanied by a depletion of ribosomal RNA subunits [ 97 ], strongly suggesting that SMUG1 might have a biologically relevant specialized function in RNA quality control. SMUG1 is also required for the maturation of hsa-let-7b-5p [ 171 ] and the maintenance of the telomerase RNA component ( hTERC ) in mammalian cells [ 170 ], apparently by regulating levels of modified RNA bases at the 3′-end of hTERC RNA, a region known to be methylated at C323 and C445 [ 172 ]. In cells, SMUG1 deficiency led to a reduction in telomerase activity (although TERT expression was not compromised), telomere attrition, perturbed localization of Dyskerin, and fragile telomeres [ 170 ].…”