HECTD1 regulates the expression of SNAIL: Implications for epithelial‑mesenchymal transition

Abstract

As a transcription factor, SNAIL plays a crucial role in embryonic development and cancer progression by mediating epithelial-mesenchymal transition (EMT); however, post-translational modifications, such as ubiquitination, which control the degradation of SNAIL have been observed to affect its functional role in EMT. In a previous study by the authors, it was demonstrated that the HECT domain E3 ubiquitin ligase 1 (HECTD1) regulated the dynamic nature of adhesive structures. In the present study, HECTD1 was observed to interact with SNAIL and regulate its stability through ubiquitination, and the knockdown of HECTD1 increased the expression levels of SNAIL. HECTD1 was discovered to contain putative nuclear localization and export signals that facilitated its translocation between the cytoplasm and nucleus, a process regulated by epidermal growth factor (EGF). Treatment with leptomycin B resulted in the nuclear retention of HECTD1, which was associated with the loss of SNAIL expression. The knockdown of HECTD1 in HeLa cells increased cell migration and induced a mesenchymal phenotype, in addition to demonstrating sustained EGF signaling, which was observed through increased phosphorylated ERK expression levels. Under hypoxic conditions, HECTD1 expression levels were decreased by microRNA (miRNA or miR)-210. Upon the observation of genetic abnormalities in the HECTD1 gene in cervical cancer specimens, it was observed that the decreased expression levels of HECTD1 were significantly associated with a poor patient survival. Thus, it was hypothesized that HECTD1 may regulate EMT through the hypoxia/hypoxia inducible factor 1α/miR-210/HECTD1/SNAIL signaling pathway and the EGF/EGF receptor/HECTD1/ERK/SNAIL signaling pathway in cervical cancer. On the whole, the data of the present study indicated that HECTD1 serves as an E3 ubiquitin ligase to mediate the stability of SNAIL proteins.

An epithelial–mesenchymal transition-related long noncoding RNA signature correlates with the prognosis and progression in patients with bladder cancer

“…There are three types of EMT (type 1, 2, and 3) which exert different functions. Type 1 occurs in the embryonic stage and is related to the growth and development of the embryo [ 16 ]. Type 2 participates in wound healing, tissue regeneration and organ fibrosis [ 17 ].…”

Structural Insights into Ankyrin Repeat-Containing Proteins and Their Influence in Ubiquitylation

“…The activation of EMT is essential during development, but it can also be triggered in various cancers through influencing cell-cell adhesion and metastasis [ 58 ]. HECTD1 contains eight nuclear localization sequences (NLS) and four nuclear export signals (NES), giving rise to its presence within the nucleus despite typical cytoplasmic localization; this localization is specifically mediated through exportin 1 (XPO1) [ 59 ]. With this ability to translocate from the cytosol to the nucleus, HECTD1 is able to regulate zinc finger protein SNAIL1 (SNAIL) expression levels.…”

Decreased HECTD1 mRNA expression is associated with poor prognosis and enhanced mitochondrial cellular respiratory function in breast cancer

“…Based on the downregulation of HECTD1 mRNA in tumor tissues (Fig. 1) and the previous reports showing that HECTD1 suppressed EMT 10,11 , we investigated the association between HECTD1 mRNA expression and tumor aggressiveness in the NCU cohort. HECTD1 mRNA expression was signi cantly lower in larger tumors (P=0.009) and higher-grade tumors (grade 3 vs. grade 1, P<0.001; grade 3 vs. grade 2, P<0.001; grade 2 vs. grade 1, P=0.042) (Fig.…”

“…HECTD1 was previously shown to play crucial roles in the negative regulation of cell [7][8][9][10] migration. A recent report demonstrated that HECTD1 negatively regulates epithelial-mesenchymal transition (EMT), resulting in decreased invasion and metastasis in breast cancer 11 .…”