Lei Zeng

Class IIa histone deacetylase 7 (HDAC7) regulates transcription primarily through scaffolding functions, but its molecular mechanisms in cancer pathogenesis remain incompletely understood. Here, we establish HDAC7 as a key epigenetic regulator in colorectal cancer (CRC). HDAC7 is overexpressed in CRC tumors and correlates with advanced disease stages, lymph node metastasis, and poor patient survival. Mechanistically, HDAC7 scaffolds a repressive complex with HDAC3 and the stress-responsive transcription factor ATF3. This reduces H3K27ac/H3K18ac occupancy and blocks BRD4/RNA polymerase II (Pol II) recruitment at ATF3 regulatory regions to epigenetically silence its transcription. Consequently, this repression inactivates ATF3's tumor-suppressive functions, activating oncogenic PI3K-Akt signaling while suppressing the Hippo pathway. Genetic depletion or pharmacological inhibition of HDAC7 disrupts this repressive complex, triggering a functional switch in ATF3. This promotes BRD4/Pol II recruitment and H3K27ac enrichment at the ATF3 locus, enabling ATF3 to undergo transcriptional self-activation. Reactivated ATF3 suppresses CRC proliferation and survival by downregulating Bcl-2, upregulating p21 (CDKN1A) to induce cell cycle arrest, promoting caspase-3-mediated apoptosis, and inhibiting PI3K-Akt signaling. Xenograft studies confirm that HDAC7 depletion suppresses tumorigenicity in vivo. Our work identifies HDAC7 as a molecular mediator that governs ATF3's functional plasticity through competitive cofactor recruitment, positioning HDAC7 inhibition as a therapeutic strategy to reactivate ATF3-mediated tumor suppression in CRC.

Colorectal cancer (CRC) remains a therapeutic challenge due to chemoresistance that limits conventional treatment efficacy. We developed ZBH-01, a camptothecin derivative engineered to target both topoisomerase I (TOP1) and DNA G-quadruplexes (G4s). Unlike irinotecan (CPT-11), which requires metabolic activation, ZBH-01 directly stabilizes TOP1-DNA covalent complexes and preferentially binds the hTERT promoter G4, a regulator of telomere maintenance and oncogenic transcription. Structural studies reveal that the crescent-shaped scaffold of ZBH-01 π-π stacks onto the external G-tetrad of the hTERT G4, displacing SP1/MYC transcription factors and suppressing hTERT expression. Functionally, ZBH-01 demonstrated improved efficacy in chemoresistant models, exhibiting 14-fold and 7-fold greater efficacy than CPT-11 and SN-38 respectively in cisplatin-resistant cells, and outperforming CPT-11 by 61-fold and SN-38 by 2.4-fold in 5-FU-resistant models. By concurrently disrupting DNA repair through TOP1-trapping and transcriptional adaptation via G4-stabilization, ZBH-01 induced DNA damage, telomere shortening, and cellular senescence. These findings establish TOP1/G4 dual-targeting as a potential therapeutic strategy to enhance CRC chemosensitivity, presenting a new framework for combining DNA damage induction with transcription modulation.

Histone lactylation couples glycolytic metabolism to oncogenic transcription, but its mechanistic readers remain poorly defined. Here, we identify bromodomain-containing protein 9 (BRD9) as a lactyl-lysine reader that links lactate-driven H3K18 lactylation (H3K18la) to chromatin remodeling in hepatocellular carcinoma (HCC). Clinically, elevated H3K18la levels correlate with poor HCC prognosis. Structural (NMR) and biophysical analyses demonstrate that BRD9’s bromodomain engages H3K18la with weak, transient affinity through its conserved acetyl-lysine pocket, distinct from its stable H3K18ac binding. This enables BRD9 to function as a metabolic-epigenetic sensor, dynamically recruited to chromatin in response to glycolytic flux. Multi-omics profiling reveals that H3K18la recruits BRD9 and the non-canonical BRG1-associated factor (ncBAF) chromatin remodeling complex to active enhancers and promoters, promoting chromatin accessibility and driving oncogenic transcription (SPARC, TMEM64, ANGEL1, SCARB1). Glycolytic inhibition or BRD9 targeting displaces BRD9 from chromatin, suppresses oncogenes, and impairs HCC proliferation. Modulating the lactylation vis p300 or HDAC inhibition attenuates transcription and reduces tumor viability. In vivo, glycolytic inhibition suppresses tumor growth. Our findings establish a feedforward loop wherein glycolytic flux promotes H3K18la-dependent BRD9-ncBAF recruitment to remodel chromatin and sustain oncogenic transcription, defining BRD9 as a critical metabolic-epigenetic mediator and a promising therapeutic target in HCC.

ASXL1 is a well-established driver of a wide range of cancers. Here, we identify a high level of genetic correlation between ASXL1 and the major transcriptional activator BRD4 in cancer cells and characterize the molecular mechanism underlying this correlation. Structural and biochemical data show the formation of a tight complex between the extraterminal domain of BRD4 and the BRD4-binding motif of ASXL1. ChIP-seq analysis of mutated ASXL1 that cannot bind BRD4 demonstrates that the recruitment of BRD4 to the ASXL1 genomic targets depends on this interaction. We find that the cancer-related truncated variants comprising residues 1-645 and 1-591 of ASXL1 (ASXL1 ^1-645 and ASXL1 ^1-591 ) retain BRD4 binding function, with ASXL1 ^1-645 showing an enhanced ability to recruit BRD4 to promoters of ASXL1 target genes. In contrast to ASXL1 ^1-591 , ASXL1 ^1-645 simultaneously and independently interacts with BRD4 and the H3K4-specific methyltransferases MLL3/4, whereas the shorter variant is lacking the MLL3/4-binding site and interacts only with BRD4. Genomic data from six cancer types reveals a strong positive ASXL1-BRD4 relationship, with BRD4 occupying the ASXL1 promoter and thus pointing to a possible feed-forward mechanism. Our findings provide mechanistic details by which ASXL1 associates with BRD4 and shed light on the biological significance of this association.

The histone H3K36-specific methyltransferase ASH1L plays a critical role in development and is frequently dysregulated in human diseases, particularly cancer. Here, we report on the biological functions of the C-terminal region of ASH1L encompassing a bromodomain (ASH1L_BD), a plant homeodomain (ASH1L_PHD) finger, and a bromo-adjacent homology (ASH1L_BAH) domain, structurally characterize these domains, describe their mechanisms of action, and explore functional crosstalk between them. We find that ASH1L_PHD recognizes H3K4me2/3, whereas the neighboring ASH1L_BD and ASH1L_BAH have DNA binding activities. The DNA binding function of ASH1L_BAH is a driving force for the association of ASH1L with the linker DNA in the nucleosome, and the large interface with ASH1L_PHD stabilizes the ASH1L_BAH fold, merging two domains into a single module. We show that ASH1L is involved in embryonic stem cell differentiation and co-localizes with H3K4me3 but not with H3K36me2 at transcription start sites of target genes and genome wide, and that the interaction of ASH1L_PHD with H3K4me3 is inhibitory to the H3K36me2-specific catalytic activity of ASH1L. Our findings shed light on the mechanistic details by which the C-terminal domains of ASH1L associate with chromatin and regulate the enzymatic function of ASH1L.

Background: Ribosomal protein SA (RPSA) of human brain microvascular endothelial cells (HBMECs) can transfer from the cytosol to the cell surface and act as a receptor for some pathogens, including Streptococcus suis serotype 2 (SS2), a zoonotic pathogen causing meningitis in pigs and humans. We previously reported that SS2 virulence factor enolase (ENO) binds to RPSA on the cell surface of HBMECs and induces apoptosis. However, the mechanism that activates RPSA translocation to the cell surface and induces ENO-mediated HBMEC apoptosis is unclear. Results: Here, we show that RPSA localization and condensation on the host cell surface depend on its internally disordered region (IDR). ENO binds to the IDR of RPSA and promotes its interaction with RPSA and vimentin (VIM), which is significantly suppressed after 1,6-Hexanediol (1,6-Hex, a widely used tool to disrupt phase separation) treatment, indicating that ENO incorporation and thus the concentration of RPSA/VIM complexes via co-condensation. Furthermore, increasing intracellular calcium ions (Ca²⁺) in response to SS2 infection further facilitates the liquid-like condensation of RPSA and aggravates ENO-induced HBMEC cell apoptosis. Conclusions: Together, our study provides a previously underappreciated molecular mechanism illuminating that ENO-induced RPSA condensation activates the migration of RPSA to the bacterial cell surface and stimulates SS2-infected HBMEC death and, potentially, disease progression. This study offers a fresh avenue for investigation into the mechanism by which other harmful bacteria infect hosts via cell surfaces’ RPSA.

Introduction: Prostate cancer (PCa) is the second most common malignancy in men. Despite multidisciplinary treatments, patients with PCa continue to experience poor prognoses and high rates of tumor recurrence. Recent studies have shown that tumor-infiltrating immune cells (TIICs) are associated with PCa tumorigenesis.Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to derive multi-omics data for prostate adenocarcinoma (PRAD) samples. The CIBERSORT algorithm was used to calculate the landscape of TIICs. Weighted gene co-expression network analysis (WGCNA) was performed to determine the candidate module most significantly associated with TIICs. LASSO Cox regression was applied to screen a minimal set of genes and construct a TIIC-related prognostic gene signature for PCa. Then, 78 PCa samples with CIBERSORT output p-values of less than 0.05 were selected for analysis. WGCNA identified 13 modules, and the MEblue module with the most significant enrichment result was selected. A total of 1143 candidate genes were cross-examined between the MEblue module and active dendritic cell-related genes.Results: According to LASSO Cox regression analysis, a risk model was constructed with six genes (STX4, UBE2S, EMC6, EMD, NUCB1 and GCAT), which exhibited strong correlations with clinicopathological variables, tumor microenvironment context, antitumor therapies, and tumor mutation burden (TMB) in TCGA-PRAD. Further validation showed that the UBE2S had the highest expression level among the six genes in five different PCa cell lines.Discussion: In conclusion, our risk-score model contributes to better predicting PCa patient prognosis and understanding the underlying mechanisms of immune responses and antitumor therapies in PCa.