Deubiquitinating Enzymes Orchestrate the Cancer Stem Cell-Immunosuppressive Niche Dialogue: New Perspectives and Therapeutic Potential

Abstract

Cancer stem cells (CSCs) are sparks for igniting tumor recurrence and the instigators of low response to immunotherapy and drug resistance. As one of the important components of tumor microenvironment, the tumor associated immune microenvironment (TAIM) is driving force for the heterogeneity, plasticity and evolution of CSCs. CSCs create the inhibitory TAIM (ITAIM) mainly through four stemness-related signals (SRSs), including Notch-nuclear factor-κB axis, Hedgehog, Wnt and signal transducer and activator of transcription. Ubiquitination and deubiquitination in proteins related to the specific stemness of the CSCs have a profound impact on the regulation of ITAIM. In regulating the balance between ubiquitination and deubiquitination, it is crucial for deubiquitinating enzymes (DUBs) to cleave ubiquitin chains from substrates. Ubiquitin-specific peptidases (USPs) comprise the largest family of DUBs. Growing evidence suggests that they play novel functions in contribution of ITAIM, including regulating tumor immunogenicity, activating stem cell factors, upregulating the SRSs, stabilizing anti-inflammatory receptors, and regulating anti-inflammatory cytokines. These overactive or abnormal signaling may dampen antitumor immune responses. The inhibition of USPs could play a regulatory role in SRSs and reversing ITAIM, and also have great potential in improving immune killing ability against tumor cells, including CSCs. In this review, we focus on the USPs involved in CSCs signaling pathways and regulating ITAIM, which are promising therapeutic targets in antitumor therapy.

Single-cell RNA-Seq Elucidates the Crosstalk Between Cancer Stem Cells and the Tumor Microenvironment in Hepatocellular Carcinoma

“…Our findings suggest the presence of aberrantly activated Hedgehog and MAPK signaling pathways in CSCs. Studies have confirmed the involvement of the Hedgehog signaling pathway [51,52] and MAPK signaling pathway [53,54] in regulating CSC differentiation and drug resistance. Importantly, by combining Monocle3 pseudotime analysis and prognostic modeling, we have discovered that HSPB1 acts as a regulatory factor in CSCs development, and its high expression indicates a poor prognosis in HCC.…”

ASB6 as an Independent Prognostic Biomarker for Colorectal Cancer Progression Involves Lymphatic Invasion and Immune Infiltration

“…As such, E3s and DUBs have emerged as promising potential drug targets for cancer therapy. Numerous studies have demonstrated that many E3s and DUBs are implicated in the initiation and progression of colorectal cancer [20][21][22][23][24][25][26][27]. However, systematic investigation into the correlation between E3s and DUBs with the prognosis of colorectal cancer holds significant clinical importance for the identification of novel prognostic markers.…”

The Role of Ubiquitin-specific Peptidases in Colorectal Cancer: A Systematic Review Protocol

“…This enzymatic function extends its influence across a broad spectrum of vital cellular functions, including the regulation of the cell cycle, facilitation of DNA repair mechanisms, orchestration of programmed cell death (apoptosis), and modulation of intricate signal transduction pathways. Within the realm of cancer research, USPs have garnered notable attention, primarily attributable to their capacity to finely tune the stability and activity levels of oncoproteins as well as tumor suppressors [12][13][14][15][16][17][18].…”