PABPC1 SUMOylation enhances cell survival by promoting mitophagy through stabilizing U-rich mRNAs within stress granules.

Stress granules (SGs) are cytoplasmic, membraneless organelles that modulate mRNA metabolism and cellular adaptation under stress, yet the mechanisms by which they regulate cancer cell survival remain unclear. Here, we identify Poly(A)-Binding Protein Cytoplasmic 1 (PABPC1), a core SG component, as stress-inducible SUMOylation target. Upon various stress conditions, SUMOylated PABPC1 promotes SG assembly and enhances cancer cell survival.

The NEXT complex regulates H3K27me3 levels to affect cancer progression by degrading G4/U-rich lncRNAs.

Polycomb repressive complex 2 (PRC2) is responsible for depositing H3K27me3 and plays essential roles in gene silencing during development and cancer. Meanwhile, the nuclear exosome targeting (NEXT) complex facilitates the degradation of numerous noncoding RNAs in the nucleoplasm. Here we find that the functional deficiency of the NEXT complex leads to an overall decrease in H3K27me3 levels.

Loss of Fbxo45 in AT2 cells leads to insufficient histone supply and initiates lung adenocarcinoma.

Dysregulation of histone supply is implicated in various cancers, including lung adenocarcinoma (LUAD), although the underlying mechanisms remain poorly understood. Here, we demonstrate that knockout of Fbxo45 in mouse alveolar epithelial type 2 (AT2) cells leads to spontaneous LUAD. Our findings reveal that FBXO45 is a novel cell-cycle-regulated protein that is degraded upon phosphorylation by CDK1 during the S/G2 phase.

A novel regulatory axis of MSI2-AGO2/miR-30a-3p-CGRRF1 drives cancer chemoresistance by upregulating the KRAS/ERK pathway.

The KRAS/ERK pathway is crucial in cancer progression and chemotherapy resistance, yet its upstream regulatory mechanism remains elusive. We identified MSI2 as a new promoter of chemotherapy resistance in cancers. MSI2 directly binds to a specific class of mature miRNAs by recognizing the 'UAG' motif and interacts with the essential effector AGO2, highlighting MSI2 as a novel regulatory factor within the miRNA pathway.

N4-acetylcytidine modifies primary microRNAs for processing in cancer cells.

N4 acetylcytidine (ac4C) modification mainly occurs on tRNA, rRNA, and mRNA, playing an important role in the expression of genetic information. However, it is still unclear whether microRNAs have undergone ac4C modification and their potential physiological and pathological functions. In this study, we identified that NAT10/THUMPD1 acetylates primary microRNAs (pri-miRNAs) with ac4C modification.

PTEN-mediated dephosphorylation of 53BP1 confers cellular resistance to DNA damage in cancer cells.

Homologous recombination (HR) repair for DNA double-strand breaks (DSBs) is critical for maintaining genome stability and conferring the resistance of tumor cells to chemotherapy. Nuclear PTEN which contains both phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and protein phosphatase plays a key role in HR repair, but the underlying mechanism remains largely elusive. We find that SUMOylated PTEN promotes HR repair but represses nonhomologous end joining (NHEJ) repair by directly dephosphorylating TP53-binding protein 1 (53BP1).

USP7 reduces the level of nuclear DICER, impairing DNA damage response and promoting cancer progression.

Endoribonuclease DICER is an RNase III enzyme that mainly processes microRNAs in the cytoplasm but also participates in nuclear functions such as chromatin remodelling, epigenetic modification and DNA damage repair. The expression of nuclear DICER is low in most human cancers, suggesting a tight regulation mechanism that is not well understood. Here, we found that ubiquitin carboxyl-terminal hydrolase 7 (USP7), a deubiquitinase, bounded to DICER and reduced its nuclear protein level by promoting its ubiquitination and degradation through MDM2, a newly identified E3 ubiquitin-protein ligase for DICER.

Regulation of SUMOylation on RNA metabolism in cancers.

Post-translational modifications of proteins play very important roles in regulating RNA metabolism and affect many biological pathways. Here we mainly summarize the crucial functions of small ubiquitin-like modifier (SUMO) modification in RNA metabolism including transcription, splicing, tailing, stability and modification, as well as its impact on the biogenesis and function of microRNA (miRNA) in particular. This review also highlights the current knowledge about SUMOylation regulation in RNA metabolism involved in many cellular processes such as cell proliferation and apoptosis, which is closely related to tumorigenesis and cancer progression.

Glucose-mediated N-glycosylation of RPTPα affects its subcellular localization and Src activation.

Receptor-type protein tyrosine phosphatase α (RPTPα) is one of the typical PTPs that play indispensable roles in many cellular processes associated with cancers. It has been considered as the most powerful regulatory oncogene for Src activation, however it is unclear how its biological function is regulated by post-translational modifications. Here, we show that the extracellular segment of RPTPα is highly N-glycosylated precisely at N21, N36, N68, N80, N86, N104 and N124 sites.

Linear ubiquitination of PTEN impairs its function to promote prostate cancer progression.

PTEN is frequently mutated in human cancers, which leads to the excessive activation of PI3K/AKT signaling and thus promotes tumorigenesis and drug resistance. Met-linked ubiquitination (M1-Ubi) is also involved in cancer progression, but the mechanism is poorly defined. Here we find that HOIP, one important component of linear ubiquitin chain assembly complex (LUBAC), promotes prostate cancer (PCa) progression by enhancing AKT signaling in a PTEN-dependent manner.

Hypoxia regulates overall mRNA homeostasis by inducing Met-linked linear ubiquitination of AGO2 in cancer cells.

Hypoxia is the most prominent feature in human solid tumors and induces activation of hypoxia-inducible factors and their downstream genes to promote cancer progression. However, whether and how hypoxia regulates overall mRNA homeostasis is unclear. Here we show that hypoxia inhibits global-mRNA decay in cancer cells.

SUMOylation of YTHDF2 promotes mRNA degradation and cancer progression by increasing its binding affinity with m6A-modified mRNAs.

N 6-Methyladenosine (m6A) is the most abundant modification within diverse RNAs including mRNAs and lncRNAs and is regulated by a reversible process with important biological functions. Human YTH domain family 2 (YTHDF2) selectively recognized m6A-RNAs to regulate degradation. However, the possible regulation of YTHDF2 by protein post-translational modification remains unknown.