A TIAM1-TRIM28 complex mediates epigenetic silencing of protocadherins to promote migration of lung cancer cells

Abstract

Lung cancer is the leading cause of cancer deaths. Its high mortality is associated with high metastatic potential. Here, we show that the RAC1-selective guanine nucleotide exchange factor T cell invasion and metastasis-inducing protein 1 (TIAM1) promotes cell migration and invasion in the most common subtype of lung cancer, non-small-cell lung cancer (NSCLC), through an unexpected nuclear function. We show that TIAM1 interacts with TRIM28, a master regulator of gene expression, in the nucleus of NSCLC cells. We reveal that a TIAM1-TRIM28 complex promotes epithelial-to-mesenchymal transition, a phenotypic switch implicated in cell migration and invasion. This occurs through H3K9me3-induced silencing of protocadherins and by decreasing E-cadherin expression, thereby antagonizing cell–cell adhesion. Consistently, TIAM1 or TRIM28 depletion suppresses the migration of NSCLC cells, while migration is restored by the simultaneous depletion of protocadherins. Importantly, high nuclear TIAM1 in clinical specimens is associated with advanced-stage lung adenocarcinoma, decreased patient survival, and inversely correlates with E-cadherin expression.

Exosome-transported circ_0061407 and circ_0008103 play a tumour-repressive role and show diagnostic value in non-small-cell lung cancer

“…TIAM1 was elevated in thyroid cancer, and its knockdown repressed thyroid cancer cell proliferation [ 45 ]. In NSCLC, TIAM1 promoted the migration and invasion of NSCLC cells through interacting with tripartite motif 28, a master regulator of gene expression in the nucleus [ 46 ]. The methylation of TIAM1 contributed to the metastasis of colon cancer and could be a predictive factor for colon cancer prognosis and a potential target for metastasis inhibition [ 47 ].…”

TRIM28 in cancer and cancer therapy

“…In NSCLC cells, TRIM28 promotes TGF-β-induced EMT by silencing E-cadherin expression, thereby promoting tumor cell migration and invasion ( Chen et al, 2014 ). Moreover, TRIM28 can form a complex with TIAM1 (T-cell invasion and metastasis-inducing protein 1) to silence E-cadherin expression and promote EMT in LC cells ( Ginn et al, 2023 ). In summary, these findings support the crucial role of TRIM28 in the different stages of LC development, and TRIM28 may be a potential clinical therapeutic target.…”

“…As discussed, TRIM28 can regulate various biological functions, including DDR ( Ziv et al, 2006 ; Goodarzi et al, 2011 ), EMT ( Venkov et al, 2007 ; Wei et al, 2016 ; Ginn et al, 2023 ), maintaining cellular stemness ( Czerwińska et al, 2017b ; Li et al, 2017 ; Han et al, 2023 ). Thus, TRIM28 is a potential target for cancer treatment.…”

Tripartite motif-containing 28 (TRIM28) expression and cordycepin inhibition in progression, prognosis, and therapeutics of patients with breast invasive carcinoma

“…By promoting the recruitment in myeloid-derived suppressor cells, TRIM28 enhances anti-PD-1 resistance in non-small cell lung cancer 15 . TRIM28 forms a complex with TIAM1 to mediate epigenetic silencing of protocadherins, thereby promoting lung cancer cell migration 16 . In ovarian cancer, TRIM28 regulates CBX8-mediated cell proliferation and tumor metastasis by recruiting E2F transcription factor 1 (E2F1) 17 .…”