Transmembrane Protein-Based Risk Model and H3K4me3 Modification Characteristics in Lung Adenocarcinoma

Abstract

The role and mechanism of transmembrane proteins (TMEMs) in tumorigenesis remain unclear. Based on 4 independent cohorts containing 1,208 cases, we identified 3 TMEMs (TMEM273, TMEM164, and TMEM125), which were used to construct a risk model to predict the prognosis of LUAD. The two patterns based on the risk score exhibited a high degree of consistency with the characteristics of immune cell infiltration and epigenetic distribution. Patients with a low-risk score, characterized by an increased activation of immunity, H3K4me3 modification, tumor cell apoptosis, chemokine secretion, and TMB, had better disease-free survival (DFS) and overall survival (OS). Obvious immunosuppression, increased epithelial–mesenchymal transition, a low H3K4me3 level, shortened cell cycle, and accelerated cell division manifested in high-risk patients, with poorer DFS and OS. The model showed a better prognostic value than the tumor immune dysfunction and exclusion score. Correlation analysis told us that patients with high scores were suitable for treatment with CD276 inhibitors for their higher levels of CD276 expression. The risk score had a strong negative correlation with HAVCR2 and ICOS among patients with EGFR-WT, KRAS-WT, STK11-WT, or TP53-MUT, and patients with these mutation types with low scores were suitable for treatment with HAVCR2 or ICOS inhibitors. This work comprehensively analyzed the role and mechanism of TMEMs in LUAD and revealed the characteristics of histone methylation modification. The TMEM-based signature gave us deep insight into immune cell infiltration profiles and provided an individualized immunotherapy strategy.

Comprehensive analysis of histone methylation modification regulators for predicting prognosis and drug sensitivity in lung adenocarcinoma

“…Until now, the functions of ZCWPW2 in tumors have not been fully studied. Fan et al revealed that a lower H3K4me3 level was associated with a poor prognosis for LUAD patients ( Fan et al, 2022 ), and we hypothesized that ZCWPW2 could maintain a higher level of H3K4me3 to play a tumor-suppressive role. Chromobox protein homolog 5 ( CBX5 ), which has been proven to be associated with silenced, heterochromatic regions of the genome and belongs to the reader of H3K9me3.…”

Development and Validation of the novel Cuproptosis- and Immune-related Signature for Predicting Prognosis in Hepatocellular Carcinoma

“…PRR11 is implicated in the regulation of Wnt expression, contributing to the proliferation and metastasis of HCC cells to some extent 38 . TMEM164, classified as a member of the transmembrane protein (TMEM) family, is characterized by its presence in various biological membranes and its independent influence on lung carcinoma prognosis 39 . The transmembrane protein 164 (TMEM164) has been shown to be involved in selective autophagosome formation during ferroptosis that is dependent on the ATG5 receptor 40 .…”

Integrating single-cell and bulk RNA sequencing to develop a cancer-associated fibroblast-related signature for immune infiltration prediction and prognosis in lung adenocarcinoma

“…IRX2 belongs to the Iroquois homeobox gene family, and there is evidence that LUADs commonly exhibit hypermethylation of the IRX2 promoter region ( 67 ). In addition, Fan et al developed a risk model based on transmembrane proteins, such as TMEM125, and explored its relationship with immune cell infiltration profiles in the TME ( 68 ). The specific mechanisms underlying the effects of TMEM125 and IRX on the development of LUAD and its prognosis warrant further investigation.…”