An integrated pathogenic framework is described that drives renal tumorigenesis via constitutive MiT/TFE nuclear accumulation and metabolic reprogramming and highlights novel therapeutic vulnerabilities targeting MiT/TFE factors and kinase rewiring, providing a rationale for organ-specific precision medicine in BHD.
Abstract
Birt-Hogg-Dubé (BHD) syndrome, caused by mutations in the tumor suppressor gene FLCN, has traditionally been classified as a classic “mTORopathy” characterized by global mTORC1 activation. Recent structural and multi-omic studies have fundamentally challenged this view, revealing that FLCN functions as a GAP for RagC/D to govern substrate-selective mTORC1 regulation. Synthesizing emerging evidence, we describe an integrated pathogenic framework: biallelic FLCN inactivation drives renal tumorigenesis via constitutive MiT/TFE nuclear accumulation and metabolic reprogramming, whereas haploinsufficiency suffices to disrupt structural integrity in the lung and skin. By reconciling the “mTORC1 paradox” through the lens of gene dosage and temporal signaling dynamics, we highlight novel therapeutic vulnerabilities targeting MiT/TFE factors and kinase rewiring, providing a rationale for organ-specific precision medicine in BHD.
This work provides a comprehensive framework that clarifies recent controversies—such as whether H4K16ac primarily governs transcription or replication timing, and which KAT8-containing complex catalyzes, which acetylation mark—and establishes a rationale for future precision-targeting strategies and biomarker development grounded in KAT8 functional heterogeneity.
Ubiquitin-specific protease 2 (USP2), a pivotal member of the deubiquitinating enzyme family, has emerged as a critical but context-dependent regulator in cancer, exhibiting paradoxical tumor-suppressive and oncogenic functions. This duality is governed by its ability to stabilize specific substrate proteins, thereby modulating central signaling hubs including the p53, Wnt/β-catenin, PI3K/Akt, and cell cycle networks. Through these axes, USP2 profoundly influences hallmark cancer phenotypes such as sustained proliferation, metabolic reprogramming, metastatic progression, immune evasion, and therapy resistance. This review systematically synthesizes the mechanistic roles of USP2 across various cancers, highlighting its function as a double-edged sword. We detail how specific interactions between USP2 and its substrates dictate its pro-tumorigenic or anti-tumorigenic outcomes, depending on the tissue and microenvironment. Furthermore, we comprehensively evaluate the landscape of emerging USP2 inhibitors, discussing their therapeutic potential and the significant challenges posed by USP2's functional duality, substrate promiscuity, and isoform diversity. Targeting USP2 presents a promising yet intricate avenue for cancer therapy, necessitating future research focused on patient stratification, combination strategies, and the development of context-specific inhibitors.
Peng Hao, Jiale Wan, Zhangyu Guo et al.· Biochimica et biophysica act...· 0 citations
Ubiquitin-specific protease 28 (USP28) is a deubiquitinating enzyme initially identified as a regulator that stabilizes p53 and c-MYC in response to DNA damage stress. Beyond its role in maintaining genomic integrity and cell cycle checkpoints, USP28 is implicated in diverse pathological processes. In various solid tumors, including lung, pancreatic, ovarian, and hepatocellular carcinomas, USP28 is markedly upregulated; it promotes proliferation, metabolic reprogramming, invasion, and therapeutic resistance by stabilizing oncoproteins such as c-Myc, STAT3, and SOX9. Conversely, in specific contexts like breast cancer and certain melanomas, USP28 deficiency drives malignant progression, revealing a context-dependent functional duality. These findings underscore the complexity of USP28 signaling and highlight its potential as a therapeutic target for precision medicine. This review summarizes the molecular characteristics and physiological functions of USP28, its context-dependent roles in neoplastic diseases, and its translational implications for targeted therapy and biomarker discovery.
Tongyong Luo, Shuncai Wu, Qingsong Wang et al.· Frontiers in Immunology· 0 citations
ABSTRACT F‐box protein 11 (FBXO11), a critical component of the F‐box protein family, serves as the substrate recognition subunit of the Skp1‐Cul1‐F‐box (SCF) E3 ubiquitin ligase complex, orchestrates the ubiquitination and proteasomal degradation of a diverse array of substrates, thereby regulating various physiological and pathological processes. Emerging evidence reveals that FBXO11 is aberrantly expressed in multiple tumor types. Predominantly, FBXO11 functions as a potent tumor suppressor, and its downregulation is strongly correlated with tumor initiation, aggressive progression, and poor prognoses. Mechanistically, FBXO11 deficiency facilitates tumor development and metastasis by deregulating the cell cycle progression, enhancing cell migration and invasion, and driving epithelial‐mesenchymal transition (EMT). However, the broad substrate spectrum of FBXO11 dictates its context‐dependent roles in cancer biology, imparting significant challenges to its direct therapeutic targeting, as systemic modulation may yield unpredictable off‐target or paradoxical effects. This review provides a comprehensive overview of current understanding of FBXO11 in oncology. By critically appraising its substrate diversity and functional versatility, we aim to re‐evaluate the clinical translation of FBXO11, proposing that it be regarded not merely as a straightforward therapeutic target, but rather as a prognostic biomarker and a context‐specific vulnerability that necessitates precision medicine strategies for effective clinical intervention.
Yuqi Zhang, Changyi Fan, Shiheng Chen et al.· Cancer Science· 0 citations
Threonine tyrosine kinase (TTK) also known as MonoPolar Spindle 1 (Mps1) is a core regulator of the spindle assembly checkpoint (SAC) that ensures accurate chromosome segregation during mitosis. While its canonical role in safeguarding genomic stability is well established, emerging evidence indicates that TTK is frequently overexpressed across a wide range of cancers, where it supports tumor cell survival under conditions of elevated chromosomal instability (CIN). This paradox highlights TTK's dual role as both a guardian of mitotic fidelity and a facilitator of tumor adaptability. Recent studies have demonstrated that pharmacological inhibition of TTK induces mitotic catastrophe by exacerbating chromosome mis-segregation, thereby selectively targeting cancer cells. Several small-molecule TTK inhibitors have entered clinical evaluation, particularly in combination with chemotherapeutic agents and radiotherapy. However, therapeutic responses remain heterogeneous, and the mechanistic basis of tumor-specific reliance on TTK across different cancer contexts remains poorly understood. This review consolidates current knowledge of TTK function beyond its canonical SAC activity, emphasizing its emerging roles in DNA damage response, epithelial-mesenchymal transition, and oncogenic signaling pathways. In addition, the review highlights critical unresolved questions, including the distinction between kinetochore and non-kinetochore functions, and the quantitative thresholds of TTK activity required for checkpoint maintenance. Finally, current advances in TTK-targeted drug development, challenges related to therapeutic selectivity and resistance, along with rational combination therapies and biomarker-guided therapeutic strategies have been summarized. Addressing these challenges will be critical for translating TTK biology into effective therapeutic interventions and for harnessing its potential in precision oncology.
Prachi Patidar, Kritika Jangir, Chainsee Saini et al.· Cell Communication and Signa...· 0 citations
Breast cancer continues to present formidable clinical challenges, particularly in triple-negative and endocrine-resistant subtypes where adaptive stress mechanisms drive therapeutic failure. Nuclear protein 1 (NUPR1), an intrinsically disordered protein, has emerged as a non-mutational hub that has been implicated in integrating metabolic, transcriptional, and cell-survival signals associated with malignant progression. This Review examines how NUPR1 transduces mitogenic stimuli into anabolic programs, while orchestrating autophagic flux, lysosomal biogenesis, and ferroptosis evasion to maintain cellular fitness under oncogenic and therapeutic stress. We discuss its causal roles in endocrine and chemoresistance through chromatin-associated cooperation with estrogen receptor α, activation of DNA-damage repair, and cell-cycle checkpoint control, as well as its contributions to metastatic dissemination via extracellular vesicle-mediated niche remodeling and immunosuppressive macrophage polarization. Furthermore, we evaluate emerging therapeutic avenues, from small-molecule inhibitors and single-domain antibody degraders that disrupt NUPR1 nuclear trafficking, to metabolic drug repurposing strategies such as statins that intercept the insulin–NUPR1 axis. Elucidating NUPR1 biology represents a paradigm shift toward targeting dynamic, stress-adaptive dependencies in breast cancer, offering new precision-oncology opportunities.
Bo Xiang, Tao Liu, Duo Xu et al.· Frontiers in Physiology· 0 citations