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Regulating nuclear export precisely is essential for maintaining mRNA homeostasis and impacts tumor progression. However, the mechanisms governing nuclear mRNA export remain poorly elucidated. Herein, it is revealed that the enhanced hypoxic long no‐ncoding RNA (lncRNA prostate cancer associated transcript 6 (PCAT6) in breast cancer (BC) promotes the nuclear export of m6A‐modified mRNAs, bolstering breast cancer stem cells (BCSCs) stemness and doxorubicin resistance. Clinically, hypoxic PCAT6 correlates with malignant BC features and poor prognosis. Mechanically, PCAT6 functions as a scaffold between interferon‐stimulated gene 15 (ISG15) and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1), leading to ISGylation of hnRNPA2B1, thus protecting hnRNPA2B1 from ubiquitination‐mediated proteasomal degradation. Interestingly, as an m6A reader, hnRNPA2B1 selectively mediates m6A‐tagged mRNAs nuclear export via the Aly/REF export factor (ALYREF)/ nuclear RNA export factor 1 (NXF1) complex, which promotes stemness‐related genes expression. HnRNPA2B1 knockdown or mRNA export inhibition can result in the retention of nuclear m6A‐tagged mRNA associated with stemness maintenance, which suppresses BCSCs self‐renewal and effectively improves the efficacy of doxorubicin therapy. These findings demonstrate the pivotal role of m6A‐modified mRNA nuclear export in BC progression, highlighting that the inhibition of m6A‐tagged mRNA and its nuclear export is a potential therapeutic strategy for the amelioration of cancer chemotherapy. [ABSTRACT FROM AUTHOR]

The regulation of PD‐L1 is the key question, which largely determines the outcome of the immune checkpoint inhibitors (ICIs) based therapy. However, besides the transcription level, the protein stability of PD‐L1 is closely correlated with its function and has drawn increasing attention. In this study, EZH2 inhibition enhances PD‐L1 expression and protein stability, and the deubiquitinase ubiquitin‐specific peptidase 22 (USP22) is identified as a key mediator in this process. EZH2 inhibition transcriptionally upregulates USP22 expression, and upregulated USP22 further stabilizes PD‐L1. Importantly, a combination of EZH2 inhibitors with anti‐PD‐1 immune checkpoint blockade therapy improves the tumor microenvironment, enhances sensitivity to immunotherapy, and exerts synergistic anticancer effects. In addition, knocking down USP22 can potentially enhance the therapeutic efficacy of EZH2 inhibitors on colon cancer. These findings unveil the novel role of EZH2 inhibitors in tumor immune evasion by upregulating PD‐L1, and this drawback can be compensated by combining ICI immunotherapy. Therefore, these findings provide valuable insights into the EZH2‐USP22‐PD‐L1 regulatory axis, shedding light on the optimization of combining both immune checkpoint blockade and EZH2 inhibitor‐based epigenetic therapies to achieve more efficacies and accuracy in cancer treatment. [ABSTRACT FROM AUTHOR]

This article, published in Advanced Science, discusses the role of EZH2 inhibitors in colorectal cancer. The study found that EZH2 inhibitors can activate the expression of deubiquitinase USP22, which stabilizes the PD-L1 protein and enhances its expression. This leads to immune evasion and compromised anti-tumor efficacy. The article suggests that combining EZH2 inhibitors with immunotherapy can overcome these immune suppressive effects and improve treatment outcomes. The full details of the study can be found in the article by Hao Wang, Jianling Yang, Lixiang Xue, and their colleagues. [Extracted from the article]