Science China Life Sciences最新文献

Gynecological cancer poses a serious threat to women's health. Despite significant advances in immunotherapy and targeted therapeutic strategies for gynecological cancers, substantial challenges persist, including limited response rates, inevitable resistance, and adverse effects. In recent years, a milestone in gynecological cancer therapy has been the approval of antibody-drug conjugates (ADCs). In this review, we provide a comprehensive overview of the structural features, mechanisms of action, and molecular characteristics of ADCs that have been approved and are currently under development. Their clinical applications and associated challenges have also been highlighted. Finally, we discuss the prospects of ADCs in the treatment of gynecological cancers.

Polycystic ovary syndrome (PCOS) is the most prevalent ovulatory and endocrine disorder affecting reproductive-aged women, yet the absence of a specific, rapid molecular diagnostic marker results in diagnostic delays and inaccuracies. Given the critical role of RNA modifications in disease pathology, this study utilized a high-throughput RNA modification profiling platform to investigate 15 types of peripheral blood RNA modification patterns in individuals with ovulatory disorders, including PCOS and primary ovarian insufficiency (POI), and control subjects. Our results revealed that distinct modification profiles correspond to specific disease states, with significant shifts in RNA modification inter-correlations observed across conditions. Additionally, specific RNA modifications were associated with clinical features, such as serum levels of testosterone and the follicle number per ovary (FNPO). To optimize diagnostic precision, we evaluated various machine learning models, identifying that combining m⁶A and m⁷G modifications in a light gradient boosting machine model (LightGBM) achieves the highest accuracy in distinguishing PCOS, outperforming traditional diagnostic markers. This highlights the potential of RNA modification profiling as a novel, high-accuracy diagnostic tool for PCOS in clinical settings.

N⁶-methyladenosine (m⁶A) in RNA within R-loops plays pivotal roles in transcription regulation and genome stability. However, the precise impacts and distinct mechanisms of m⁶A on both regulatory and aberrant R-loops remain poorly understood. Here, we reveal that METTL3, the nuclear m⁶A writer, ensures genome integrity by differentially modulating R-loops in a position- and length-dependent manner. In mouse embryonic stem cells (mESCs), Mettl3 depletion results in impaired cell proliferation and increased cell death due to excessive DNA damage. Notably, Mettl3 knockout reduces the overall abundance of R-loops, with a decrease in broad R-loops and an increase in sharp R-loops. R-loops are diminished near transcription end sites (TESs), leading to transcriptional readthrough of genes with m⁶A-modified transcripts and potentially contributing to genome instability. Conversely, increased sharp R-loops located in the antisense orientation relative to gene transcription are associated with DNA damage hotspots. These findings unveil a dual regulatory mechanism in which METTL3-m⁶A orchestrates transcription fidelity and genome stability through distinct R-loop-dependent manners.

The specific mechanisms of N⁶-methyladenosine (m⁶A) in castration-resistant prostate cancer (CRPC) remain incompletely understood. Wilms' tumor 1 and pyruvate kinase M2-like protein (WTAP) serve as a major regulatory factor of m⁶A. However, whether it regulates CRPC through m⁶A mechanisms is unclear. This research revealed that WTAP stands out as a key regulator among m⁶A factors, and considerably influences the development and behavior of CRPC. WTAP was downregulated in CRPC. A low WTAP expression predicts poor survival and a high WTAP promotes the flutamide drug sensitivity of CRPC cells. WTAP-modulated m⁶A modification, which can be recognized by YTHDF2, contributes to the post-transcriptional inactivation of nuclear receptor subfamily 3 group C member 1 (NR3C1). In vitro and in vivo experiments unveiled the key role of NR3C1, a rarely studied oncoprotein, in CRPC. The WTAP/YTHDF2/NR3C1 axis was actively involved in CRPC malignancy and the flutamide drug sensitivity of CRPC cells. The clinical correlation of WTAP, YTHDF2, and NR3C1 was further demonstrated in CRPC tissues and castration-dependent prostate cancer tissues. Our study uncovered a novel molecular mechanism by which the m⁶A-induced WTAP/YTHDF2/NR3C1 axis promotes CRPC flutamide drug sensitivity. This finding suggests the potential of WTAP as a promising prognostic marker and therapeutic target against flutamide drug sensitivity in CRPC.

Investigations from the last four decades have correlated high O-linked N-acetylglucosamine (O-GlcNAc) levels with various cancer types, but it is not known how OGT responds to diverse nutrients to finetune cellular O-GlcNAcylation levels. Herein we identified a critical OGT phosphorylation site by unc-51 like autophagy activating kinase 1 (ULK1) under glucose depletion. First, we demonstrated that glucose levels modulate the interaction between OGT and ULK1 and cellular O-GlcNAcylation levels. Low glucose induces high O-GlcNAcylation, which could be reversed by ULK1 inhibition. Then, using mass spectrometry, we showed that ULK1 phosphorylates OGT at Ser576 and stabilizes OGT. Further biochemical experiments revealed that Ser576 phosphorylation inhibits Lys604 ubiquitination by stimulating OGT binding with BAP1, a de-ubiquitinase for OGT. Strikingly, using the OGT^S576A knock-in cells, we found that in mouse xenograft models OGT-S576A completely abolishes the tumorigenicity of OGT, probably due to low O-GlcNAcylation. In sum, we found that ULK1 phosphorylates OGT at Ser-576 under glucose deprivation, which stabilizes OGT by promoting OGT-BAP1 association and is pivotal for O-GlcNAcylation levels and tumorigenesis. As low glucose is often associated with tumor progression, our work not only unearths a key mechanism of how OGT is regulated by glucose levels, but also offers new therapeutic opportunities targeting OGT.

Metabolic reprogramming is a hallmark of cancer, playing a critical role in tumorigenesis by supporting cancer cell survival, proliferation, metastasis, and immune evasion. Oncogenic signaling pathways regulate key metabolic processes by orchestrating gene expression and enhancing metabolic enzyme activity, ensuring cancer cells meet their bioenergetic and biosynthetic demands. Here, we highlight the roles of major oncogenic metabolic signaling pathways, including phosphoinositide 3-kinase (PI3K)/AKT, Myc, p53, and hypoxia-inducible factor (HIF), in driving metabolic rewiring. We provide a conceptual framework to understand why metabolic reprogramming occurs in tumor cells, how metabolic alterations contribute to tumorigenesis, metastasis, and immune evasion, and the therapeutic implications of targeting these metabolic vulnerabilities in cancer.