Ubiquilin proteins regulate EGFR levels and activity in lung adenocarcinoma cells

Abstract

Ubiquilin (UBQLN) proteins are involved in diverse cellular processes like endoplasmic reticulum‐associated degradation, autophagy, apoptosis, and epithelial‐to‐mesenchymal transition. UBQLNs interact with a variety of substrates, including cell surface receptors, transcription factor regulators, proteasomal machinery proteins, and transmembrane proteins. In addition, previous work from our lab shows that UBQLN1 interacts with insulin‐like growth factor receptor family members (IGF1R, IGF2R, and INSR) and this interaction regulates the activity and proteostasis of IGFR family members. We wondered whether UBQLN proteins could also bind and regulate additional receptor tyrosine kinases. Thus, we investigated a link between UBQLN and the oncogene epidermal growth factor receptor (EGFR) in lung adenocarcinoma cells. Loss of UBQLN1 occurs at high frequency in human lung cancer patient samples and we have shown that the loss of UBQLN1 is capable of altering processes involved in cell proliferation, migration, invasion, and epithelial‐to‐mesenchymal transition in lung adenocarcinoma cell lines. Here, we present data that loss of UBQLN1 resulted in increased turnover of total EGFR while increasing the relative amount of phosphorylated EGFR in lung adenocarcinoma cells, especially in the presence of its ligand EGF. Furthermore, the loss of UBQLN1 led to a more invasive cell phenotype as manifested by increased proliferation, migration, and speed of movement of these lung adenocarcinoma cells. Taken together, UBQLN1 regulates the expression and stability of EGFR in lung cancer cells.

Abnormally elevated ubiquilin‑1 expression in breast cancer regulates metastasis and stemness via AKT signaling

“…To further elucidate the biological role of UBQLN1 in breast cancer, the influence of UBQLN1 knockdown on biological behavior in vitro was investigated, in particular regarding metastasis. In contrast to the tumor suppressor role reported in lung cancer cells ( 6 , 11 , 35 ), the present study found that the knockdown of UBQLN1 inhibited cell migration and invasion, EMT, and MMP2 and MMP9 expression in breast cancer cell lines. EMT has been implicated in carcinogenesis, and confers metastatic properties to cancer cells by enhancing mobility and invasion ( 37 ).…”

“…UBQLN1 is abnormally expressed in certain cancer types, including lung adenocarcinoma ( 11 , 18 ) and gastric cancer ( 12 ). In the present study, to elucidate UBQLN1 expression in breast cancer, UBQLN1 expression was detected in a tissue array slide, containing samples from 73 breast cancer cases and 30 normal breast tissues by using IHC.…”

“…While the total number of cases included in the IHC analysis in present study was relatively small, including only 1 case with stage IV, further more well-characterized largescale studies are required to validate the association of UBQLN protein expression with the distant metastasis of breast cancer. UBQLN1 expression has been estimated in several cancer types, including non-small cell lung cancer (NSCLC) ( 6 , 11 , 34 – 36 ), and breast ( 20 ), gastric ( 12 ) and ovarian cancer ( 19 ). The majority of the findings in the literature cited above are consistent with the findings of the present study, suggesting that UBQLN1 promotes cancer progression and may play an oncogenic role in cancer.…”

“…UBQLN1 has been observed to be absent and underexpressed in ~50% of tumor tissues ( 6 ). The silencing of UBQLN1 in a NSCLC cell line has been shown to increase cell proliferation, migration and invasion, actin cytoskeleton reorganization, and the induction of EMT, leading to a more invasive cell phenotype ( 6 , 11 , 35 ). These data raise doubts concerning the biological role of UBQLN1 in cancer, and further research is therefore warranted to clarify the role of UBQLN1 in cancer.…”

“…Ubiquilin-1 (UBQLN1) belongs to a family of ubiquitin-like proteins that contain five major UBQLN proteins (UBQLN1-4 and UBQLNL). These proteins are evolutionarily conserved and structurally similar, containing an amino-terminal ubiquitin-like (UBL) domain, a carboxy-terminal ubiquitin-associated (UBA) domain and a series of four chaperonin-like domains within the central part of the protein ( 6 , 11 ). The UBL domain mediates interaction with the proteasome, whereas the UBA domain preferentially binds to ubiquitinated proteins ( 12 ).…”