Breast cancer metastasis remains the leading cause of disease-related mortality, yet the regulatory mechanisms enabling tumor cells to adapt to distant tissue environments remain poorly defined. Here, we generated a multi-omic resource integrating transcriptomic (RNA-seq) and chromatin accessibility (ATAC-seq) profiles from estrogen receptor-positive primary breast tumors and matched liver and lung metastases obtained from the same patients, including diagnostic and postmortem specimens. This design enabled direct intra-patient comparisons of primary and metastatic regulatory landscapes. We identified extensive reprogramming of chromatin accessibility and gene expression in metastatic lesions relative to primary tumors, indicating widespread regulatory remodeling. Peak-to-gene correlation analysis uncovered thousands of metastasis-associated enhancer-gene linkages, with metastatic samples exhibiting significantly increased enhancer connectivity. These rewired enhancer networks preferentially targeted clinically relevant genes, including RIPK4 , ISYNA1, and RAB3D, which were associated with three or more enhancers in metastases but not in primary tumors. Furthermore, ATAC-seq footprinting combined with gene expression analysis revealed distinct, tissue-specific transcription factor activity profiles in liver and lung metastases, including ESR1, that were not explained by transcription factor expression levels alone. Together, these data provide a resource of metastasis-specific regulatory elements and their cognate transcription factors, revealing new regulatory vulnerabilities that may be therapeutically exploitable. Implications: These findings support a model in which breast cancer metastasis is driven by enhancer regulatory reprogramming, allowing tumor cells to adapt to a variety of microenvironments.
Oral squamous cell carcinoma (OSCC) is a lethal malignancy characterized by frequent metastasis. Utilizing a 4-NQO-induced murine model and single-cell RNA sequencing, we identified a distinct Collagen Type I Alpha 1 Chain (Col1a1+) epithelial subpopulation that is significantly expanded in OSCC, exhibits the highest epithelial-mesenchymal transition (EMT) signature, and correlates with poor patient survival. Functional studies demonstrated that Col1a1 knockdown in OSCC cell lines (HSC3, SCC25) attenuated TGF-β-induced EMT, impaired migration and invasion in vitro, and reduced tumor burden in a conditional knockout mouse model. Transcriptomic profiling following Col1a1 silencing revealed the suppression of TGF-β signaling and ECM-receptor interaction pathways. We further identified BMP1 as a key downstream effector, demonstrating a direct physical interaction between COL1A1 and BMP1, and showed that COL1A1 potentiates BMP1's proteolytic activity. Rescue experiments confirmed that BMP1 is essential for COL1A1-driven tumor growth, metastasis, and TGF-β pathway activation in vivo. Furthermore, we uncovered an immunomodulatory role for the COL1A1-BMP1 axis, whereby it promotes M2 macrophage polarization via TGF-β secretion to foster an immunosuppressive tumor microenvironment. This effect was reversible using either BMP1 knockdown or TGF-β neutralization. In conclusion, our study establishes a novel COL1A1-BMP1-TGF-β signaling cascade that drives OSCC progression by autonomously enhancing tumor cell malignancy and non-autonomously reprogramming the immune landscape, nominating this axis as a promising therapeutic target. Implications: These findings identify a novel COL1A1-BMP1 axis driving both OSCC malignancy and immunosuppression, offering potential diagnostic markers and therapeutic targets for the clinic.
ERG fusions occur in about 50% of prostate cancers (PCa) and represent early somatic events that co-initiate tumorigenesis. Yet, the molecular programs unleashed by ERG at disease onset remain elusive. Here, the inducible, temporally controlled expression of ERG enabled the accurate mapping of early ERG-driven processes associated with an apparent decrease in cell fitness across a panel of prostate cells. We observed that ERG triggers senescence and epithelial-mesenchymal transition (EMT), generating distinct cellular states in which EMT and senescence coexist in the same cell or occur independently. ERG-mediated activation of canonical and non-canonical TGF beta signaling differentially regulates EMT and senescence markers. Moreover, ERG drives context-dependent changes in cell identity and promotes an intermediate basal-luminal cell population with stem cell gene expression. Notably, p53 loss enhances ERG-driven expression of cell plasticity markers without affecting senescence. Transcriptomic investigation of ERG-expressing epithelial cells revealed activation of inflammatory signals. Conditioned medium experiments demonstrated paracrine-mediated inflammation in epithelial ERG-negative, stromal, and myeloid cells. Consistently, patient-derived expression data from 5 independent cohorts and 2,048 men showed activation of TNFA-NFKB and TGF beta signaling in ERG-rearranged tumors. Further, deconvolution analysis indicated a higher infiltration of inflammatory macrophages in ERG-positive tumors. Altogether, we uncovered a previously unrecognized triad of ERG-driven processes -dedifferentiation, senescence, and inflammation- that may underpin its oncogenic potential and shape PCa initiation and therapeutic response. Implications: Temporal control of ERG expression in prostate cells enabled accurate mapping of ERG-driven processes, identifying dedifferentiation, senescence, and inflammation as candidate contributors to ERG-dependent tumorigenesis and therapeutic response.
Desmoplastic small round cell tumors (DSRCTs) are rare, aggressive, fusion-driven sarcomas with poor outcomes despite intensive chemotherapy. Utilization of targeted therapies in DSRCT remains limited, underscoring the need for deeper characterization of patient tumors. To address this, we performed multi-omic profiling on nine patient-derived tumor biopsies from five patients enrolled in a precision oncology program. We consistently observed elevated mRNA and protein expression of human epidermal growth factor receptor 2 (HER2), androgen receptor (AR), and DNA damage response (DDR) markers, and characterized these molecular features using an integrated assay suite including bulk and single-cell RNA sequencing, protein profiling, immunohistochemistry, immune analyses, and functional homologous recombination deficiency (HRD) testing. We define a replication stress-associated DNA damage landscape and identify functional HRD in a subset of tumors lacking genomic HRD scar signatures. Single-cell analyses reveal intra- and intertumoral heterogeneity, while longitudinal sampling uncovers treatment-dependent shifts in expression and activity that may contribute to adaptive resistance. The immune microenvironment is characterized by dysfunctional T-cell states and sparse antigen-presenting cells. Collectively, these analyses delineate recurrent, biologically targetable features and patient-specific vulnerabilities, establishing a foundation for biomarker-guided therapeutic strategies in DSRCT. These findings support the investigation of rational combination approaches informed by sensitive detection methods and functional testing to address resistance in ultra-rare cancers. Implications: Integrative multi-omic profiling combined with functional testing in DSRCT reveals patient-specific vulnerabilities and biologically targetable receptor and DNA damage response dependencies, while defining immune states that may inform therapeutic response and rational combination strategies in this rare, fusion-driven cancer.
Stomach adenocarcinoma (STAD) is among the most prevalent malignant gastrointestinal tumors worldwide. Ferroptosis, a relatively new form of programmed cell death, has garnered significant attention for its role in cancer molecular mechanisms and therapeutic strategies. Therefore, it is particularly important to explore the mechanism of key molecules in ferroptosis on STAD. In our study, CUGBP Elav-like family member 1 (CELF2) was identified to be lowly expressed in STAD tumor tissues at both mRNA and protein levels. Next, CELF2 effectively inhibited the growth and migration of STAD cells both in vitro and in vivo. RNA-seq analysis of AGSCELF2 and AGSNC cells showed that the functions of differentially expressed genes were enriched in the glutathione metabolism and ferroptosis pathway. CELF2 increased the levels of key ferroptosis markers, including ROS, MDA, Fe²⁺ and 4-HNE, while reducing GSH levels. Furthermore, CELF2 enhanced the susceptibility of STAD tumor cells to ferroptosis. Interestingly, the expression levels of CELF2 and Solute carrier family 7 member 11 (SLC7A11) were negatively correlated in RNA-seq data and TCGA database. RIP and RNA pull-down assays confirmed the interaction between CELF2 and SLC7A11. Overexpression of SLC7A11 reversed the effects of CELF2 on STAD growth and ferroptosis levels. Moreover, Ferroptosis inhibitor Ferrostatin-1 effectively rescued the inhibitory effect of CELF2 overexpression on proliferation of tumor cells. CELF2 is a tumor suppressor that promotes the level and susceptibility of ferroptosis in STAD cells by targeting SLC7A11. Implications: This study offers valuable molecular insights for the development of ferroptosis-targeted therapies for STAD.
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy primarily driven by oncogenic KRAS signaling. The splicing factor SRSF1 plays a key oncogenic role in PDAC through reciprocal cross-interactions with KRAS signaling. However, the mechanisms regulating SRSF1 protein stability remain poorly understood. Here, we identify the deubiquitinase USP39 as a critical regulator of SRSF1 stability. It interacts with SRSF1 in an RNA-independent manner and suppresses its ubiquitination. USP39 is upregulated in PDAC and correlates with poor patient prognosis. Functional analyses demonstrate that USP39 promotes PDAC cell progression, in part through stabilization of SRSF1. Mechanistically, MYC activates USP39 transcription through direct promoter binding. These findings define a MYC-USP39-SRSF1 regulatory axis that integrates transcriptional and post-translational mechanisms in PDAC and suggest USP39 as a potential therapeutic target. Implications: USP39 functions as a central regulator that integrates transcriptional and post-translational regulation in pancreatic cancer through the MYC-USP39-SRSF1 axis and represents a potential therapeutic target.
Abstract Kallikrein 2 (KLK2) and six-transmembrane epithelial antigen of the prostate 1 (STEAP1) are two cell surface targets with relevance for prostate cancer therapy. The objective of this study was to characterize the expression landscape of KLK2 and STEAP1 in metastatic castration-resistant prostate cancer (mCRPC) and to define associated transcriptomic, genomic, and epigenomic features. We analyzed a total of 1,095 patient samples from three mCRPC cohorts, including in situ studies of rapid autopsy cases and patient-derived xenograft models. We found that KLK2 and STEAP1 expression is strongly enriched in androgen receptor (AR)–positive tumors and largely absent in neuroendocrine and double-negative phenotypes. Within AR+ tumors, pairwise comparisons revealed coexpression and high combined positivity rates for STEAP1, KLK2, and prostate-specific membrane antigen, suggesting that cotargeting any two of these antigens increases overall tumor coverage. Analysis of samples from a rapid autopsy cohort, which enabled assessment of intra- and intertumoral diversity, showed comparable degrees of expression heterogeneity for KLK2 and STEAP1. Antigen expression correlated positively with AR genomic alterations and serum prostate-specific antigen levels and negatively with RB1 and PTEN loss. Transcriptomic and epigenome analyses demonstrated distinct mechanisms governing antigen expression: KLK2 showed a strict AR dependence with coordinated AR/FOXA1/HOXB13 binding and enhancer activation, whereas STEAP1 was only partially AR-dependent and additionally regulated by locus-specific DNA methylation changes. Furthermore, KLK2 and STEAP1 expression states were associated with distinct transcriptional programs and immune microenvironmental features. Implications: These findings establish KLK2 and STEAP1 as key prostate adenocarcinoma-lineage antigens and provide critical insights to inform the rational design and clinical development of cell surface antigen–directed therapies in prostate cancer.
Triple-negative breast cancer (TNBC) is an aggressive malignancy with high mortality and limited treatment options, yet the role of YTH domain-containing protein 1 (YTHDC1) in its progression remains unclear. In this study, we investigated the function and mechanism of YTHDC1 in TNBC using in vitro assays, including quantitative real-time polymerase chain reaction, Western blot, cell counting kit-8, colony formation, and sphere formation assays, to assess cell proliferation and stemness. Fluorescence in situ hybridization and RNA immunoprecipitation (RIP) were performed to examine YTHDC1 binding to BTB domain and CNC homology 1 (BACH1) mRNA, and actinomycin D treatment was used to evaluate BACH1 mRNA stability upon YTHDC1 silencing. Additionally, rescue experiments further assessed whether BACH1 overexpression could reverse the effects of YTHDC1 knockdown. We found that YTHDC1 was significantly upregulated in TNBC tissues and cells. Silencing YTHDC1 suppressed cell proliferation, colony formation, and sphere formation and reduced the expression of stemness markers (Nanog, Oct4, and SOX2). Mechanistically, YTHDC1 silencing inhibited the nuclear export of BACH1 mRNA, leading to an increased nucleoplasmic ratio. RIP assays further revealed the enrichment of both YTHDC1 and N6-methyladenosine (m6A) modifications on BACH1 mRNA, and YTHDC1 knockdown significantly decreased BACH1 mRNA stability. Importantly, BACH1 overexpression rescued the inhibitory effects of YTHDC1 silencing on TNBC cell proliferation and stemness marker expression. Together, these findings demonstrate that YTHDC1 regulates BACH1 expression through an m6A-dependent mechanism, thereby contributing to TNBC progression. IMPLICATIONS:Our findings provide a rationale for further investigation of the YTHDC1-BACH1 axis as a potential therapeutic target in TNBC.
Abstract Gastric cancer is a common malignant tumor of the digestive tract. Chemotherapy resistance severely limits the therapeutic effect of this disease. The competing endogenous RNA regulatory network is widely involved in the occurrence and development of various cancers and is also closely related to the generation of drug resistance. However, the underlying molecular mechanism remains to be further elucidated. This study investigated the molecular mechanism by which the long noncoding RNA SNHG15/miR-451a/Caveolin-1 (CAV1) axis mediates oxaliplatin resistance in gastric cancer through regulating fatty acid β-oxidation. Through analysis using The Cancer Genome Atlas database and qRT-PCR, it was found that SNHG15 was highly expressed in gastric cancer tissues, whereas miR-451a was lowly expressed. Bioinformatics prediction combined with dual luciferase and RNA immunoprecipitation experiments confirmed that SNHG15 could act as a molecular sponge for miR-451a, and CAV1 was the downstream target gene of miR-451a. Functional experiments demonstrated that the knockdown of miR-451a or overexpression of CAV1 could promote cell proliferation, inhibit apoptosis, and alleviate G0–G1-phase arrest while enhancing fatty acid β-oxidation. In vivo experiments further confirmed that the SNHG15/miR-451a/CAV1 axis affected gastric cancer oxaliplatin resistance by regulating fatty acid β-oxidation. Implications: This study revealed that SNHG15 inhibits miR-451a to upregulate CAV1 expression, thereby regulating fatty acid β-oxidation and influencing gastric cancer oxaliplatin resistance, providing new biomarkers and potential therapeutic targets for gastric cancer oxaliplatin resistance.
An aberration in cellular, especially plasma membrane (PM), cholesterol level is arguably the most critical targetable hallmark of colorectal cancer and colorectal cancer stem cell (CRCSC) phenotypes. We recently identified Star-related lipid transfer protein 5 (StarD5) as an intracellular cholesterol transport protein that regulates PM cholesterol levels. In this study, we show that StarD5 protein levels are significantly elevated in most human colorectal cancer tissues compared with adjacent normal mucosa, with a preferential increase in the epithelial compartment. Additionally, allograft growth in StarD5 knockout mice was largely unaffected. StarD5 levels were particularly elevated in CRCSCs compared with non-CRCSCs in several colon cancer cell lines and primary human colorectal cancer samples. Genetic knockdown of StarD5 (shRNA; KD) inhibited the CRCSC phenotype in vitro-growth and self-renewal (1°→3° spheroid formation), CRCSC maker levels, and sensitivity to 5-fluorouracil. Also, StarD5-depleted HT-29 cells showed a robust (40-fold) reduction in tumor formation (CRCSC characteristics) in vivo and CRCSC phenotype ex vivo, including CRCSC marker expression and spheroid formation (1°→3°). StarD5 inhibition also caused a significant increase in apoptosis induction. Mechanistically, PM cholesterol levels were significantly higher in CRCSCs than in non-CRCSCs, and StarD5 depletion decreased accessible PM cholesterol, particularly in specialized lipid raft domains. Finally, cholesterol depletion in the PM is critical for StarD5 KD's inhibition of the CRCSC phenotype as supplementation with low-density lipoprotein caused a significant reversal of the StarD5 KD effects on PM/raft cholesterol levels and the CRCSC phenotype. IMPLICATIONS:Given StarD5's critical role in regulation of CRCSCs, translational research targeting StarD5 will lead to improved outcomes in patients with colorectal cancer.
Osteosarcoma remains a highly aggressive malignant tumor with strong metastatic potential and limited therapeutic options. E3 ubiquitin ligases, particularly the HECT-type family, regulate oncogenic pathways via targeted protein degradation. Among them, Itchy E3 ubiquitin protein ligase (ITCH) has been implicated in poor prognosis in multiple cancers. However, its functional effects and clinical relevance in osteosarcoma pathogenesis remain completely unexplored. Herein, ITCH expression in osteosarcoma tissues was detected using qRT-PCR, Western blot, and IHC. In vitro and in vivo, the function of ITCH was evaluated by soft agar colony formation assay, Transwell assay, CCK8 assay, wound healing assay, immunofluorescence, flow cytometric analysis, and xenograft tumor assay. Downstream targets were further investigated using proteomic analysis, Western blot, and immunoprecipitation. ITCH was aberrantly overexpressed in osteosarcoma tissues, exhibiting a strong negative correlation with patient survival. Mechanistically, ITCH directly bound P53 and mediated its ubiquitination and degradation. ITCH-driven P53 loss enhanced malignant phenotypes, whereas ITCH knockdown restored P53 stability. This study demonstrates that ITCH functions as an oncogene in osteosarcoma by targeting P53 for degradation and suggests ITCH as a promising therapeutic target. IMPLICATIONS:These findings define a molecular mechanism underlying the oncogenic role of ITCH through P53 ubiquitination-dependent degradation.
In tumor cells, DNA replication is constantly challenged by endogenous and exogenous sources, referred to as replication stress, and various pathways have evolved to mitigate this stress in cancer. We recently identified an extracellular matrix (ECM)-induced DNA repair pathway involving N-myc downstream regulated gene 1 (NDRG1). Matrix-induced signaling results in NDRG1-dependent protection from chemotherapy-induced replication stress. To uncover further mechanistic details of NDRG1-mediated effects on DNA replication, we identified transglutaminase 2 (TGM2) as a novel NDRG1-binding partner. TGM2 is an acyltransferase that catalyzes Ca(2+)-dependent protein modifications. This interaction was enriched upon chemotherapy-induced replication stress and also upon ECM-induced signaling. Our data show that TGM2 depletion significantly slows replication fork progression, and this phenotype is dependent on TGM2 catalytic activity and its nuclear localization. Our study further identifies a putative NDRG1-TGM2 binding site and shows that the physical interaction between NDRG1 and TGM2 is required for efficient DNA replication.Implications: This study reveals a previously unrecognized nuclear function for NDRG1 and TGM2 in regulating DNA replication fork stability and recovery, and uncovers a stress-responsive mechanism that supports replication homeostasis in cancer cells and advances our understanding of how extracellular signals are integrated with replication and repair pathways.
Abstract Cancer remains one of the most pressing global health challenges, with immunotherapy being a promising treatment option. However, numerous clinical challenges, such as recurrence and resistance, persist, underscoring the urgent need for a deeper understanding of the mechanisms that influence immune responses in cancer. Polo-like kinases (PLK), a family of enzymes with five members, PLK1 through PLK5, have been implicated in cancer progression, and their inhibition is being actively explored for cancer management. Although past studies of the PLK family are largely confined to their role in the cell cycle and corresponding chromatin dynamics, recent research has unveiled important connections between PLKs and cancer immunity, particularly in relation to critical signaling pathways such as interferon (IFN) signaling, immunogenic cell death, transforming growth factor beta (TGFβ) signaling, and FAS/FASL signaling. Although much of the research has focused on PLK1, additional members of the PLK family are beginning to attract attention due to their potential implications in cancer immunity. Understanding the intricate role of PLKs in cancer immunity is an emerging field with tremendous potential. This review offers a comprehensive overview of current knowledge connecting the members of the PLK family with cancer immunology and provides considerations for further research to uncover how PLK signaling can be strategically targeted to optimize cancer immunotherapy and enhance clinical responses.
The P47S missense germline variant of TP53 exists in approximately 2% of Americans of African descent and may account for the increased cancer risk and poorer response to therapy evident in African-descent populations. In this work, we sought to identify personalized therapeutic approaches for cancer containing the P47S variant, with a focus on the most common cancer evident in the P47S mouse, liver cancer. We identify the microtubule-targeting agents lexibulin, colchicine, and combretastatin A-4 as three compounds that bind to the colchicine-binding pocket of the α/β-tubulin dimer, and which show increased efficacy in a P47S liver cancer cell line compared with parental cells with wild-type p53. We find evidence for an unusual mechanism underlying this increased efficacy: Our data indicate that the P47S variant shows increased ability to bind to the peptidyl-prolyl isomerase PIN1; this leads to decreased PIN1-cyclin D1 complexes in P47S cells, along with increased cell-cycle arrest in response to lexibulin. IMPLICATIONS:These findings support the growing literature that particular mutant forms of TP53 may have specific therapeutic vulnerabilities that can be targetable; improved understanding of these unique vulnerabilities can lead to improved understanding of p53 function.
Brain cancers are among the most lethal and challenging malignancies to treat in the clinic. An important impediment to effectively treat brain tumors is the blood-brain tumor barrier (BTB), an interface generated between the blood-brain barrier and intracranial tumors, creating a tumor-permissive perivascular microenvironment. The BTB loses endothelial barrier properties in a heterogeneous manner across the tumor but continues to impede effective intratumoral drug delivery, dramatically decreasing the potential of many antineoplastic pharmaceutics. This review will provide a summary of our current understanding of the molecular composition and cellular architecture of the BTB, focusing on glioblastoma and other high-grade gliomas. We will summarize different multiomic and spatial studies performed with the goal to reveal unknown traits of the brain cancer-associated vasculature and identify molecular targets of therapeutic relevance. Our work aims to consolidate our current understanding of the vasculature in brain tumors and the insights held regarding its role in brain cancer biology and therapeutic drug delivery.
Pediatric cancers are frequently driven by genomic alterations that result in impaired differentiation during development. To identify complex-level dependencies required for differentiation in neuroblastoma, a pediatric cancer of the developing peripheral nervous system, we curated a list of protein complexes using the CORUM database and mined the Dependency Map using gene set enrichment analysis. This analysis identified the noncanonical polycomb repressive complex 1.1 (PRC1.1) complex, which represses transcriptional activity through ubiquitination of histone 2A, lysine 119 (H2AK119Ub), as a selectively enriched dependency in neuroblastoma. Knockout of PRC1.1 subunits reduced neuroblastoma growth by inducing a neuronal differentiation program. Although no known direct inhibitors of PRC1.1 exist, codependency analysis identified that the deubiquitinase USP7 strongly correlated with PRC1.1 dependency. Treatment with XL177A, a small molecule inhibitor of USP7, significantly reduced neuroblastoma growth in both cellular and animal models. Integrated RNA and chromatin immunoprecipitation sequencing showed that both PRC1.1 knockout and USP7 inhibition resulted in highly correlated transcriptional alterations and reduced H2AK119Ub deposition on chromatin, suggesting that USP7 inhibition reduced neuroblastoma growth through a PRC1.1-dependent mechanism. Mechanistically, global proteomics and ubiquitinomics revealed that USP7 inhibition disrupted noncanonical PRC1 complex assembly, resulting in the destabilization of PRC1.1 and subsequent proteolysis. Our findings expand our understanding of the chromatin complexes required to maintain a dedifferentiated state in neuroblastoma and suggest the therapeutic potential for USP7 inhibitors in the treatment of this disease.Implications: Our study reveals the potential for utilizing USP7 inhibitors to target epigenetic repression of differentiation programs in neuroblastoma by reducing PRC1 activity.
Circular RNA (circRNA), usually produced through a back-splicing process, is a type of single-stranded RNA that is covalently bonded. Our research indicated that a spliceosome composed of SF3B4 and QKI promoted the back-splicing of FNDC3B, thereby promoting the generation of circRNA FNDC3B (Circ-FNDC3B). Circ-FNDC3B is underexpressed in breast cancer and is characterized by a high metastatic risk. In addition, Circ-FNDC3B expression was reduced in breast cancer with larger tumor diameter, later clinical staging, and lymph node metastasis. The secondary structure of Circ-FNDC3B, specifically the 356 to 425 bp sequence, interacts with the biotin carboxylase domain of pyruvate carboxylase (PC), inhibiting the activity of PC. Low expression of Circ-FNDC3B enhances the activity of PC, thereby facilitating cell proliferation. The underlying mechanism involves the promotion of aspartate synthesis and the acceleration of the citrate-pyruvate cycle. This, in turn, promotes NADPH synthesis, thus alleviating the oxidative damage induced by reactive oxygen species. Furthermore, in human breast cancer organoids and a mouse model of lung metastasis, we have validated that exogenous expression of Circ-FNDC3B can inhibit the activity of PC, thereby suppressing tumor proliferation and promoting tumor cell apoptosis. In general, upregulating the expression of Circ-FNDC3B can impede the progression of breast cancer. IMPLICATIONS:This study reveals significant heterogeneity in the expression of circRNAs commonly used to identify breast cancer metastasis and confirms that circRNAs affect the metabolic state of breast cancer through their binding proteins.
Lenvatinib, a first-line targeted therapy for advanced hepatocellular carcinoma (HCC), exhibits significant clinical efficacy. At present, there remains a scarcity of effective treatment options for patients experiencing lenvatinib resistance. This study aims to identify and validate molecular markers capable of predicting the therapeutic response of patients with HCC to lenvatinib treatment. We successfully established a lenvatinib-resistant HCC cell line (Huh7/LR) through progressive exposure of parental Huh7 cells to lenvatinib. Through RNA sequencing analysis, ubiquitin-specific protease 43 (USP43) was ultimately pinpointed as a potential key molecule related to lenvatinib resistance. The expression of USP43 is notably elevated in lenvatinib-resistant HCC cells and tissues, correlating with a poor prognosis for HCC. USP43 promotes the proliferation of HCC cells, suppresses apoptosis, and enhances resistance to lenvatinib. Mechanistically, E26 transformation-specific 1 (ETS1) transcriptionally upregulates USP43. USP43 then binds to nonmuscle myosin heavy chain 9 (MYH9) and removes its K48-linked polyubiquitination. This stabilizes the MYH9 protein by preventing its degradation through the ubiquitin-proteasome pathway and further activates the AKT/BAD signaling axis, ultimately suppressing apoptosis and conferring lenvatinib resistance. IMPLICATIONS:Targeting the ETS1/USP43/MYH9 axis presents a promising therapeutic strategy to overcome lenvatinib resistance in HCC.
