Modification of PLAC8 by UFM1 affects tumorous proliferation and immune response by impacting PD-L1 levels in triple-negative breast cancer

Abstract

BackgroundTriple-negative breast cancer is characterized by a poor prognosis and lack of targeted treatments, and thus, new targeting markers and therapeutic strategies are urgently needed. We previously indicated that PLAC8 promotes tumorigenesis and exerts multidrug resistance in breast cancer. Therefore, we aimed to characterize the PLAC8-regulated network in triple-negative breast cancer.MethodsWe measured the levels of PLAC8 in breast cancer cell lines and found that PLAC8 is post-translationally modified by ubiquitin-fold modifier 1 (UFM1). Then, we revealed a new regulatory system of PD-L1 by PLAC8 in triple-negative breast cancer. We also tested the molecular functions of PLAC8 in triple-negative breast cancer cell lines and measured the expression of PLAC8 and PD-L1 in breast cancer tissues.ResultsPLAC8 was generally highly expressed in triple-negative breast cancer and could be modified by UFM1, which maintains PLAC8 protein stability. Moreover, PLAC8 could promote cancer cell proliferation and affect the immune response by regulating the level of PD-L1 ubiquitination. Additionally, among patients with breast cancer, the expression of PLAC8 was higher in triple-negative breast cancer than in non-triple-negative breast cancer and positively correlated with the level of PD-L1.ConclusionsOur current study discoveries a new PLAC8-regulated network in triple-negative breast cancer and provides corresponding guidance for the clinical diagnosis and immunotherapy of triple-negative breast cancer.

PLAC8-Mediated Activation of NOX4 Signalling Restores Angiogenic Function of Endothelial Colony-Forming Cells in Experimental Hypoxia

“…Of relevance to the current study, PLAC8 is highly expressed in stem cells during embryonic development [ 39 ], while suppression of PLAC8 expression promotes proliferation and regenerative capacity of pluripotent stem cells via induction of JNK-dependent signalling [ 40 ]. There are emerging reports linking PLAC8 to disease progression, including cancer [ 41 , 42 ] and diabetes [ 36 ], although specific mechanisms are poorly defined. For example, one study found PLAC8 induction to promote cell proliferation in breast cancer [ 42 ], while another reported inhibitory actions in hepatocellular carcinoma [ 43 ].…”

“…There are emerging reports linking PLAC8 to disease progression, including cancer [ 41 , 42 ] and diabetes [ 36 ], although specific mechanisms are poorly defined. For example, one study found PLAC8 induction to promote cell proliferation in breast cancer [ 42 ], while another reported inhibitory actions in hepatocellular carcinoma [ 43 ]. However, there is a paucity of understanding of the role of PLAC8 expression in endothelial progenitor cells, which appears to be limited to reported upregulation in ECFCs isolated from neonates exposed to gestational diabetes, inhibition of which led to an improved proliferation and senescence [ 36 ].…”

Investigation of Underlying Biological Association and Targets between Rejection of Renal Transplant and Renal Cancer

“…Although the precise role of PLAC8 in tumorigenesis remains unclear, recent studies have shown that PLAC8 plays multiple roles across various cell types. For example, PLAC8 induces epithelial–mesenchymal transition in colon carcinoma cells [ 36 ]; regulates PD-L1 ubiquitination levels in breast cancer cells, thus influencing immune response and cancer cell proliferation [ 37 ]; and triggers oncogenic autophagy, thus affecting autophagosome–lysosome fusion in pancreatic cells [ 38 ].…”

Modulation of the tumor microenvironment and mechanism of immunotherapy-based drug resistance in breast cancer

“…This protein is overexpressed in TNBC, and its stability is regulated by ubiquitin-fold modifier 1 (UFM1), a ubiquitination modifier [ 225 , 226 ]. PLAC8 has been reported to modify PD-L1 expression in TNBC via its ubiquitination, leading to immune tolerance [ 227 , 228 ]. Moreover, cuproptosis, non-apoptotic programmed cell death due to high intracellular copper accumulation, is involved in immune tolerance [ 229 ].…”