Network analyses elucidate the role of SMYD3 in esophageal squamous cell carcinoma

Abstract

SMYD 3 is a member of the SET and myeloid‐Nervy‐DEAF‐1 (MYND) domain‐containing protein family of methyltransferases, which are known to play critical roles in carcinogenesis. Expression of SMYD 3 is elevated in various cancers, including esophageal squamous cell carcinoma (ESCC), and is correlated with the survival time of patients with ESCC . Here, we dissect gene expression data, from a previously described KYSE 150 ESCC cell line in which SMYD 3 had been knocked down, by integration with the protein–protein interaction ( PPI ) network, to find the new potential biological roles of SMYD 3 and subsequent target genes. By construction of a specific PPI network, differentially expressed genes ( DEG s), following SMYD 3 knockdown, were identified as interacting with thousands of neighboring proteins. Enrichment analyses from the DAVID Functional Annotation Chart found significant Gene Ontology ( GO ) terms associated with transcription activities, which were closely related to SMYD 3 function. For example, YAP 1 and GATA 3 might be a target gene for SMYD 3 to regulate transcription. Enrichment annotation of the total DEG PPI network by GO ‘Biological Process’ generated a connected functional map and found 532 significant terms, including known and potential biological roles of SMYD 3 protein, such as expression regulation, signal transduction, cell cycle, cell metastasis, and invasion. Subcellular localization analyses found that DEG s and their interacting proteins were distributed in multiple layers, which might reflect the intricate biological processes at the spatial level. Our analysis of the PPI network has provided important clues for future detection of the biological roles and mechanisms, as well as the target genes of SMYD 3.

SMYD3: An Oncogenic Driver Targeting Epigenetic Regulation and Signaling Pathways

“…In cultured HCC cells, SMYD3 co-occupies the SNAI2 promoter in collaboration with the ANKHD1 protein, promoting invasion and metastasis through the SNAIL2 pathway [71]. In addition, invasion of tumors obtained from SMYD3 knocked-down KYSE150 ECC cells was much lower than that of control cells [72].…”

Playing on the Dark Side: SMYD3 Acts as a Cancer Genome Keeper in Gastrointestinal Malignancies

“…High levels of SMYD3 have also been positively correlated with STAT3 [48], MMP-9 [49] and TGFb1 [50] expression, and reported to repress the anticancer effects of sulforaphane [51]. Moreover, increased expression of SMYD3 has been found in esophageal squamous cell carcinoma, where it is associated with lymph node metastasis and poor overall survival [22][23][24]. In pancreatic adenocarcinoma, high SMYD3 levels positively correlated with tumor size, TNM stage, perineural invasion, lymph node metastasis and shorter survival [25].…”

“…Consistently, a close correlation has been observed between SMYD3 activity and the development of several malignancies. Indeed, SMYD3 has been found overexpressed in several types of cancers, including colorectal (CRC), breast (BC), gastric (GC), pancreatic (PC), ovarian (OvCa), prostate and lung cancer, and hepatocellular carcinoma (HCC) [1], with high SMYD3 levels being associated with reduced overall survival and worse prognosis [11,[20][21][22][23][24][25].…”

Long Non-coding RNAs WithIn VitroandIn VivoEfficacy in Preclinical Models of Esophageal Squamous Cell Carcinoma Which Act by a Non-microRNA Sponging Mechanism

“…SMYD3 methylates various histone and non-histone targets and plays an oncogenic role (158). In ESSC patients, expression of SYMD3 is negatively correlated with survival time (159). lncRNA PHBP1 increases expression of prohibitin.…”