FAM188B Expression Is Critical for Cell Growth via FOXM1 Regulation in Lung Cancer

Abstract

Although family with sequence similarity 188 member B (FAM188B) is known to be a member of a novel putative deubiquitinase family, its biological role has not been fully elucidated. Here, we demonstrate the oncogenic function of FAM188B via regulation of forkhead box M1 (FOXM1), another oncogenic transcription factor, in lung cancer cells. FAM188B knockdown induced the inhibition of cell growth along with the downregulation of mRNA and protein levels of FOXM1. FAM188B knockdown also resulted in downregulation of Survivin and cell cycle-related proteins, which are direct targets of FOXM1. Interestingly, FOXM1 co-immunoprecipitated with FAM188B, and the levels of FOXM1 ubiquitination increased with FAM188B knockdown but decreased with FAM188B overexpression. In addition, in vivo xenograft of FAM188B siRNA (siFAM188B) RNA-treated cells resulted in the retardation of tumor growth compared with that in the control. Furthermore, protein levels of FAM188B and FOXM1 were elevated in the human lung cancer tissues, and FAM188B expression was negatively correlated with the overall survival of lung cancer patients. These results indicate that FAM188B exerts its oncogenic effects by regulating FOXM1 deubiquitination and thus its stability. Therefore, FAM188B might be a potential therapeutic target to control lung cancer progression.

FAM188B Downregulation Sensitizes Lung Cancer Cells to Anoikis via EGFR Downregulation and Inhibits Tumor Metastasis In Vivo

“…However, FAM188B knockdown inhibited cell aggregate formation in all three cell lines with an increase in dead cells stained by PI and shown in red ( Figure 2 C). Although we used si-FAM188B RNA that has been described in our previous report [ 14 ], we also used other si-FAM188B RNAs to avoid off-target effects. As shown in Figure S2 , all three si-FAM188B RNAs reduced cell aggregate formation in the suspension culture.…”

“…In addition, FAM188B knockdown decreased cell growth in the 3D culture condition, which mimics in vivo conditions ( Figure 4 E). FAM188B knockdown decreased levels of Survivin, which is an anti-apoptotic protein that plays a critical role in anoikis resistance [ 14 ]. Recently, we reported that FAM188B knockdown decreased levels of FOXM1, an oncogenic transcription factor, with an increase in its ubiquitination in A549 cells [ 14 ].…”

“…FAM188B knockdown decreased levels of Survivin, which is an anti-apoptotic protein that plays a critical role in anoikis resistance [ 14 ]. Recently, we reported that FAM188B knockdown decreased levels of FOXM1, an oncogenic transcription factor, with an increase in its ubiquitination in A549 cells [ 14 ]. Since Survivin expression can be regulated by both STAT3 and FOXM1 [ 24 , 25 ], Survivin downregulation by si-FAM188B treatment is probably due to STAT3 inactivation and/or FOXM1 downregulation ( Figure 3 D).…”

“…We previously reported that FAM188B knockdown results in cell death via accumulation and activation of p53 in colorectal cancer cell lines [ 13 ], indicating that FAM188B expression is important for cell survival. In addition, we found that FAM188B expression is enhanced and poorly correlated with poor survival in lung cancer patients [ 14 ], indicating that FAM188B might have a role in tumorigenesis and malignancy. In this study, we evaluated, for the first time, the importance of FAM188B in the regulation of anoikis resistance.…”

ELF3 Is a Target That Promotes Therapeutic Efficiency in EGFR Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer Cells via Inhibiting PKCί

“…The 18S rRNA was used as an internal control gene for several target genes (Supplementary Table S5). Amplification was carried out (n = 3) on a LC480 real-time PCR system (Roche, Basel, Switzerland) as described in a previous report [33].…”