Pan-cancer analysis of genomic and transcriptomic data reveals the prognostic relevance of human proteasome genes in different cancer types

Abstract

Background The human proteasome gene family (PSM) consists of 49 genes that play a crucial role in cancer proteostasis. However, little is known about the effect of PSM gene expression and genetic alterations on clinical outcome in different cancer forms. Methods Here, we performed a comprehensive pan-cancer analysis of genetic alterations in PSM genes and the subsequent prognostic value of PSM expression using data from The Cancer Genome Atlas (TCGA) containing over 10,000 samples representing up to 33 different cancer types. External validation was performed using a breast cancer cohort and KM plotter with four cancer types. Results The PSM genetic alteration frequency was high in certain cancer types (e.g. 67%; esophageal adenocarcinoma), with DNA amplification being most common. Compared with normal tissue, most PSM genes were predominantly overexpressed in cancer. Survival analysis also established a relationship with PSM gene expression and adverse clinical outcome, where PSMA1 and PSMD11 expression were linked to more unfavorable prognosis in ≥ 30% of cancer types for both overall survival (OS) and relapse-free interval (PFI). Interestingly, PSMB5 gene expression was associated with OS (36%) and PFI (27%), and OS for PSMD2 (42%), especially when overexpressed. Conclusion These findings indicate that several PSM genes may potentially be prognostic biomarkers and novel therapeutic targets for different cancer forms.

Proteasome inhibition induces DNA methylation alteration by attenuating the synthesis of DNA methyltransferase 1 and 3B in colorectal cancer

“…Interestingly, knockdown of either DNMT resulted in the downregulation of specific core components of the proteasome machinery (Fig. 4G-H), which are also the targets of PIs (Larsson et al, 2022; Yadav et al, 2023), potentially reducing vulnerability to PIs. Above all, these data support the protective role of DNMT1 and DNMT3B downregulation against proteasome inhibition in CRC through modulation of the cellular transcriptome.…”

Pan-caner analysis identifies PSMA7 as a targets for amplification at 20q13.33 in tumorigenesis

“…In the past years, the correlation between elevated PSMA7 expression with adverse prognosis was reported by sporadic research 12 , 21 – 28 . Recently, a TCGA-based pan-cancer study mentioned briefly the prognostic valus of 49 proteasome family member genes including PSMA7 59 , which indeed serves as a significant precursor to our own research. During the explorations of CNA of chr20 using similar genomic data from TCGA tumors, we identified PSMA7 as the most potential target at the newly found amplicon of 20q13.33.…”

“…Then we at a pan-cancer level systematically explored the status of amplification and expression of the PSMA7 gene and their clinical significances in terms of prognosis and potential therapeutic opportunity. Distinguishing from the previous pan-cancer research focusing on the prognostic values of PSMA7 59 , we further investigated the underlying mechanism linking high PSMA7 expression to poor prognosis. Analysis of proteins interacting or genes correlating with PSMA7 revealed broad functions of PSMA7 in multiple cellular processes 13 , especially networks with proteasome binding or complex.…”

DNAJA4 suppresses epithelial-mesenchymal transition and metastasis in nasopharyngeal carcinoma via PSMD2-mediated MYH9 degradation

“…In this study, we found that the proteasomal noncatalytic subunit PSMD2 interacted with MYH9 and induced its degradation via the ubiquitin-proteasome pathway in NPC. PSMD2, proteasome 26 S subunit ubiquitin receptor/ non-ATPase 2, is reported to be a key ubiquitin-proteasome-related gene for predicting prognosis in multiple cancer types [ 56 – 58 ]. PSMD2 physically interacts with p21 and p27 and mediates their degradation via the ubiquitin-proteasome pathway by cooperating with the deubiquitinating enzyme USP14, subsequently promoting cell proliferation and facilitating cell cycle progression in breast cancer [ 59 ].…”