TRIM26 promotes non-small cell lung cancer survival by inducing PBX1 degradation

Abstract

The transcription factor PBX1 is regarded as an oncogene in various cancers, but its role in non-small cell lung cancer (NSCLC) and the detailed mechanism is not known. In the present study, we found that PBX1 is downregulated in NSCLC tissues and inhibits NSCLC cell proliferation and migration. Subsequently, we performed an affinity purification-coupled tandem mass spectrometry (MS/MS) and found the ubiquitin ligase TRIM26 in the PBX1 immunoprecipitates. Moreover, TRIM26 binds to and mediates PBX1 for K48-linked polyubiquitination and proteasomal degradation. Noticeably, TRIM26 activity depends on its C-terminal RING domain when it is deleted TRIM26 loses its function towards PBX1. TRIM26 further inhibits PBX1 transcriptional activity and downregulates the PBX1 downstream genes, such as RNF6. Moreover, we found that overexpression of TRIM26 significantly promotes NSCLC proliferation, colony formation, and migration in contradiction to PBX1. TRIM26 is highly expressed in NSCLC tissues and predicts poor prognosis. Lastly, the growth NSCLC xenografts is promoted by overexpression of TRIM26 but is suppressed by TRIM26 knockout. In conclusion, TRIM26 is a ubiquitin ligase of PBX1 and it promotes while PBX1 inhibits NSCLC tumor growth. TRIM26 might be a novel therapeutic target for the treatment of NSCLC.

Tripartite motif-containing protein 26 promotes colorectal cancer growth by inactivating p53

“…A parallel effect was observed in glioblastoma as revealed by Mahlokozera, Patel et al who found that TRIM26 stabilizes SOX2 protein and enhances its oncogenic activity in glioblastoma via its C-terminal PRYSPRY domain without engaging its Ring domain and E3 ligase activity ( 11 ). Moreover, the oncogenic influence of TRIM26 was also detected in non-small cell lung cancer (NSCLC) by Sun, Lin et al The study pointed that TRIM26 serves as an ubiquitin ligase for PBX1, and depletion of TRIM26 hindered NSCLC growth ( 23 ).…”

Advances of E3 ligases in lung cancer

“…Tripartite motif containing 26 (TRIM26) suppresses phosphorylation of PI3K p85 and AKT, leading to inhibition of proliferation in NSCLC cells [ 80 ]. Besides, TRIM26 can interact with and induce K48-linked polyubiquitination and proteasomal degradation of Pre-B cell leukemia transcription factor 1 (PBX1), leading to inhibition of proliferation and migration in NSCLC cells [ 81 ]. Tripartite motif containing 28 (TRIM28) induces cisplatin resistance by promoting proliferation and suppressing apoptosis in NSCLC cells [ 82 ], TRIM28 also polyubiquitinates and induces proteasome-mediated degradation of E3 ring finger protein, LIM domain interacting (RLIM, also called RNF12) while promoting the stability of murine double minute 2 (MDM2), causing degradation of p53 and upregulation of proliferation, migration and invasion in NSCLC cells [ 83 ].…”

PBX1: a TALE of two seasons—key roles during development and in cancer

“…Sexual developmental defects; CAKUTHED (Mary et al, 2022) Endometrial Carcinoma: Tumor suppressor (Guo et al, 2023) Ovarian Cancer: Oncogene (Park et al, 2008), chemoresistance (Jung et al, 2016) Prostate Cancer: Proliferation (Kikugawa et al, 2006;Liu et al, 2019b) Renal Clear Cell Carcinoma: Cell proliferation via JAK2/STAT3 signaling (Wei et al, 2018) Bladder Cancer: Cell growth, invasion, EMT (Zhao et al, 2022) Gastrointestinal system/ digestive tract Gut aplasia in Pbx1 −/− mice (Selleri et al, 2001) Gastric Carcinoma: potential oncogene (upregulation of miR650 and EMT) (Liu et al, 2021); potential tumor suppressor (upregulation of its PBXIP1 inhibitor) (He et al, 2017) Colorectal Cancer: Metastasis inhibition (Dai et al, 2023) Mouse model of hepatocellular carcinoma: tumor suppressor (upregulation of its PBXIP1 inhibitor) (Xu et al, 2013) Pancreas and pancreatic islands development (Kim et al, 2002) Diabetes mellitus (suggested) (Kim et al, 2002) Lung Lungs development (Li et al, 2014) Non-Small Cell Lung Cancer: Proliferation promotion (Lin et al, 2022) or tumor suppression (Sun et al, 2023) Lymphangioleiomyomatosis: cell survival by inducing expression of antiapoptotic genes (Olatoke et al, 2023) Lung hypoplasia (Mary et al, 2022) Brain Differentiation of olfactory bulb, mesencephalic and midbrain dopaminergic neurons (Sgadò et al, 2012;Remesal et al, 2020); hindbrain segmentation through control of RA synthesis (Vitobello et al, 2011) Brain cancer. Neuroblastoma: higher expression levels in the initial tumor samples compared with responders (Veselska et al, 2019); Glioma: tumor suppressor role) (van Vuurden et al, 2014) Parkinson: reduced levels in dopaminergic neurons (Villaescusa et al, 2016) Other ectoderm derivatives Epithelial cells: Corneal morphogenesis (Murphy et al, 2010); modulation of body-site-specific epidermal barrier (seen with Pbx1 epidermal-specific null mice), auditory sensory epithelium (Li et al, 2020b) Oral squamous cell carcinoma: Oncogene…”