Biology subjects

Chang, H.-Y.

Publications and source records attributed to Chang, H.-Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Machine learning prediction of eukaryotic hosts for giant viruses

Giant viruses (GVs; Nucleocytoviricota) infect diverse eukaryotes and are ecologically important across ecosystems. Although cultivation-independent sequencing has recovered tens of thousands of GV genomes from environmental samples, eukaryotic hosts are only known for a few isolates, leaving the host contexts of most GVs elusive. We developed GVHoP (Giant Virus-Host Predictor) that predicts eukaryotic hosts from GV genomes by integrating gene content and GV-eukaryotic sequence similarities. Trained on isolates with experimentally identified hosts, GVHoP achieved 97% accuracy in cross-validation and predicts hosts at three hierarchical levels of eukaryote classification. Functional analyses link top predictive features to various processes involved in virus-host interactions, including viral entry, replication, morphogenesis, and cellular metabolic reprogramming. Applying GVHoP to 7,897 GV metagenome-assembled genomes assigned hosts to 5,280 viruses and uncovered potential novel hosts across major GV orders that cannot be inferred from core-gene phylogenetic information. The predicted host composition clearly separates aquatic and terrestrial environments and distinct aquatic ecosystems. Together, GVHoP links viruses known only from nucleic acid sequences to their putative hosts across the eukaryotic tree of life, improves our understanding of GV-host interactions and their potential impacts on ecosystems, and paves the way for further ecological and functional studies of environmental GVs.

microbiology↗

bioRxiv2026

Distinct subcellular localizations of DUF1218 proteins in Marchantia polymorpha and Nicotiana benthamiana reveal two different plasmodesmata-targeting mechanisms

Plasmodesmata are membrane-lined channels connecting plant cells to facilitate intercellular transport of molecules. Although many plasmodesmata-localized proteins have evolved throughout plant evolution, whether they use a conserved targeting system remains unclear. In the bryophyte Marchantia polymorpha, we identified two DUF1218-domain proteins homologous to the Arabidopsis plasmodesmata-localized AtTVA. When ectopically expressed, MpDUF1218-1 localized to plasmodesmata in both Nicotiana benthamiana and M. polymorpha, whereas MpDUF1218-2 formed cytoplasmic puncta in both species. Unexpectedly, AtTVA formed cytoplasmic puncta rather than localizing to plasmodesmata in M. polymorpha. Domain-swap analyses revealed that the first helix of MpDUF1218-1 is crucial for plasmodesmata localization in N. benthamiana, while the first two helices are required in M. polymorpha. In contrast, the second and third helices of AtTVA contribute to its plasmodesmata localization in N. benthamiana. Further domain dissection indicated that other regions of MpDUF1218-1 also contribute to accurate targeting by regulating its distribution among the ER, cytoplasmic puncta, and plasma membrane. Together, our findings suggest that MpDUF1218-1 is targeted by a mechanism shared between the two species, whereas AtTVA relies on a distinct mechanism present in N. benthamiana but absent in M. polymorpha, suggesting the emergence of alternative plasmodesmata-targeting pathways during land plant evolution.

plant biology↗

bioRxiv2026

The SPARK complex forms the molecular basis of vertebrate fertilization

Fertilization requires gamete recognition and membrane fusion, yet the molecular basis of this process in vertebrates remains unknown. Here we identify SPARK (sperm protein assembly and receptor-binding key), a conserved multi-protein complex that integrates all known sperm fertilization factors, including TMEM81-IZUMO1-SPACA6 and DCST1/2, together with two newly identified components, TMDD1 and FAM187A. SPARK subunits are mutually dependent for stability in mature sperm, and disruption of any single component causes male sterility in zebrafish and mice. Incubating zebrafish sperm with soluble egg receptor Bouncer partially rescues fertilization of Bouncer-deficient eggs in a SPARK-dependent manner, consistent with egg receptor binding priming the complex for fusion. Thus, we propose SPARK as a con-served molecular machine that couples gamete recognition to membrane fusion.

developmental biology↗

bioRxiv2025

Analysis of isobaric quantitative proteomic data using TMT-Integrator and FragPipe computational platform

Isobaric mass tags, such as iTRAQ and TMT, are widely utilized for peptide and protein quantification in multiplex quantitative proteomics. We present TMT-Integrator, a bioinformatics tool for processing quantitation results from TMT and iTRAQ experiments, offering integrative reports at the gene, protein, peptide, and post-translational modification site levels. We demonstrate the versatility of TMT-Integrator using five publicly available TMT datasets: an E. coli dataset with 13 spike-in proteins, the clear cell renal cell carcinoma (ccRCC) whole proteome and phosphopeptide-enriched datasets from the Clinical Proteomic Tumor Analysis Consortium, and two human cell lysate datasets showcasing the latest advances with the Astral instrument and TMT 35-plex reagents. Integrated into the widely used FragPipe computational platform (https://fragpipe.nesvilab.org/), TMT-Integrator is a core component of TMT and iTRAQ data analysis workflows. We evaluate the FragPipe/TMT-Integrator analysis pipelines performance against MaxQuant and Proteome Discoverer with multiple benchmarks, facilitated by the bioinformatics tool OmicsEV. Our results show that FragPipe/TMT-Integrator quantifies more proteins in the E. coli and ccRCC whole proteome datasets, identifies more phosphorylated sites in the ccRCC phosphoproteome dataset, and delivers overall more robust quantification performance compared to other tools.

bioinformatics↗

bioRxiv2025

Comparative Transcriptomics Reveals Context- and Strain-Specific Regulatory Programs of Agrobacterium During Plant Colonization

Agrobacterium is a genus of plant-associated bacteria capable of transferring DNA into host genomes to induce tumorigenesis. The process has been primarily studied in a few model strains, particularly C58, and developed into Agrobacterium-mediated transformation (AMT) for genetic manipulation. However, the diversity of wild-type strains and their context-specific regulatory responses remain poorly characterized. Here, we evaluated five wild-type strains and identified 1D1108 as superior in tumorigenesis on legumes and transient transformation in Nicotiana benthamiana. Under in vitro virulence induction with acetosyringone (AS), we identified 126 differentially expressed genes (DEGs) in 1D1108. Although the number of DEGs was comparable to those in C58 and the legume isolate 1D1609 under the same condition, only 22 DEGs, primarily within the vir regulon, were conserved, indicating extensive divergence among these Agrobacterium strains. Leaf infiltration of N. benthamiana revealed 1,134 DEGs specifically regulated in planta for 1D1108. These included genes involved in attachment, virulence regulation, type IV pilus, succinoglycan biosynthesis, and diverse nutrient transporters, providing new evidence on expression regulation during colonization. Comparative analyses of in planta transcriptomes with C58 and Pseudomonas syringae DC3000 revealed distinct secretion systems required for pathogenesis, namely type IV for Agrobacterium and type III for Pseudomonas, and only approximately 5-19% of DEGs were conserved. These limited transcriptomic overlaps underscore the importance of studying gene expression in strains and conditions directly relevant to the biological context, rather than relying on model systems. Together, this work reveals how environmental and host-associated cues shape transcriptional responses in plant-associated bacteria. IMPORTANCEAgrobacterium is a key tool for plant genetic engineering, yet much of our knowledge about its biology comes from a few strains studied under artificial conditions. This work combines tumor formation assays on legumes and transient transformation in Nicotiana benthamiana with transcriptomic analyses to explore how diverse Agrobacterium strains, particularly the high-performing wild-type strain 1D1108, respond to host and environmental cues. By comparing gene expression under in vitro and in planta conditions, we found that the bacterial response within plant tissue is more complex than previously appreciated. Cross-strain comparisons further revealed limited conservation in gene expression regulation, even under similar conditions. Comparative analysis with Pseudomonas syringae revealed the activation of distinct secretion systems for pathogenesis and differences in regulatory programs used during plant colonization. These findings underscore the importance of studying bacteria in biologically relevant contexts and highlight the limitations of relying solely on model strains to infer regulatory responses.

microbiology↗

bioRxiv2025

Transcriptomic and chromatin accessibility profiling unveils new regulators of heat hormesis in Caenorhabditis elegans

Heat hormesis describes the beneficial adaptations resulting from transient exposure to mild heat stress, which enhances stress resilience and promotes healthy aging. While heat hormesis is widely observed, much remains to be learned about its molecular basis. This study bridges a critical knowledge gap through a comprehensive multiomic analysis, providing key insights into the transcriptomic and chromatin accessibility landscapes throughout a heat hormesis regimen in C. elegans. We uncover highly dynamic, dose-dependent molecular responses to heat stress and reveal that while most initial molecular changes induced by mild stress revert to baseline, key differences emerge in response to subsequent heat shock challenge that likely contribute to physiological benefits. We further demonstrate that heat hormesis extends lifespan specifically in wild-type animals, but not in germlineless mutants, likely due to transient disruption of germline activities during mild heat exposure, which appears sufficient to trigger pro-longevity mechanisms. This finding points to tissue-specific responses in mediating the physiological outcomes of heat hormesis. Importantly, we identify several highly conserved regulators of heat hormesis that likely orchestrate gene expression to enhance stress resilience. Among these regulators, some (MARS-1/MARS1, SNPC-4/SNAPc, FOS-1/c-Fos) are broadly required for heat hormesis-induced benefits, whereas others (ELT-2/GATA4, DPY-27/SMC4) are uniquely important in specific genetic backgrounds. This study advances our understanding of stress resilience mechanisms, points to multiple new avenues for future investigations, and provides a molecular framework for promoting healthy aging through strategic mid-life stress management.

genomics↗

bioRxiv2025

Comparative genomic analysis of a novel heat-tolerant and euryhaline strain of unicellular marine cyanobacterium Cyanobacterium sp. DS4 from a high-temperature lagoon

BackgroundCyanobacteria have diversified through their long evolutionary history and occupy a wide range of environments on Earth. To advance our understanding of their adaption mechanisms in extreme environments, we performed stress tolerance characterizations, whole genome sequencing, and comparative genomic analyses of a novel heat-tolerant and euryhaline strain of the unicellular cyanobacterium Cyanobacterium sp. Dongsha4 (DS4). This strain was isolated from a lagoon on Dongsha Island in the South China Sea, a habitat with fluctuations in temperature, salinity, light intensity, and nutrient supply. ResultsDS4 cells can tolerate long-term high-temperature up to 50 and salinity from 0 to 6.6 %, which is similar to the results previously obtained for Cyanobacterium aponinum. In contrast, most mesophilic cyanobacteria cannot survive under these extreme conditions. Based on the 16S rRNA gene phylogeny, DS4 is most closely related to Cyanobacterium sp. NBRC 102756 isolated from Iwojima Island, Japan, and Cyanobacterium sp. MCCB114 isolated from Vypeen Island, India. For comparison with strains that have genomic information available, DS4 is most similar to Cyanobacterium aponinum strain PCC 10605 (PCC10605), sharing 81.7% of the genomic segments and 92.9% average nucleotide identity (ANI). Gene content comparisons identified multiple distinct features of DS4. Unlike related strains, DS4 possesses the genes necessary for nitrogen fixation. Other notable genes include those involved in photosynthesis, central metabolisms, cyanobacterial starch metabolisms, stress tolerances, and biosynthesis of novel secondary metabolites. ConclusionsThese findings promote our understanding of the physiology, ecology, evolution, and stress tolerance mechanisms of cyanobacteria. The information is valuable for future functional studies and biotechnology applications of heat-tolerant and euryhaline marine cyanobacteria.

genomics↗

bioRxiv2024

Exploring The Formation And Permeability Of Plasmodesmata In The Liverwort, Marchantia polymorpha

Plasmodesmata are cell-wall-embedded channels that evolved in the common ancestor of land plants to increase cell-to-cell communication. Whether all the fundamental properties of plasmodesmata emerged and were inherited in all land plants at the same time is unknown. Here we show that the bryophyte Marchantia polymorpha (a non-vascular plant) forms mostly simple plasmodesmata in early-developing gemmae. The complexity of plasmodesmata increases during gemma maturation, and complex plasmodesmata with enlarged cavities are majorly observed in thalli. In contrast to vascular plants, whose simple plasmodesmata can transport monomeric fluorescent proteins, plasmodesmata in Marchantia polymorpha limited their permeability before the juvenile-to-adult transition. In support, callose, a known polysaccharide regulating plasmodesmata permeability in vascular plants, accumulated in most of the Marchantia polymorpha tissues examined. Furthermore, we found that in the apical meristematic region, plasmodesmata allowed the transport of monomeric fluorescent proteins, and this relaxation might correlate with the lower accumulation of callose. Taken together, our study suggests that certain plasmodesmata properties, such as complexity progression and callose accumulation, may have evolved before the divergence between vascular and non-vascular plants.

plant biology↗

bioRxiv2024

Population genomics of a thermophilic cyanobacterium revealed divergence at subspecies level and possible adaptation genes

BackgroundCyanobacteria are diverse phototrophic microbes with ecological importance and potential for biotechnology applications. One species of thermophilic cyanobacteria, Thermosynechococcus taiwanensis, has been studied for biomass pyrolysis, estrogen degradation, and the production of bioethanol, monosaccharide, and phycocyanin. To better understand the diversity and evolution of this species, we sampled across different regions in Taiwan for strain isolation and genomic analysis. ResultsA total of 27 novel strains were isolated from nine of the 12 hot springs sampled and subjected to whole genome sequencing. Including strains studied previously, our genomic analyses encompassed 32 strains from 11 hot springs. Genome sizes among these strains ranged from 2.64 to 2.70 Mb, with an average of 2.66 Mb. Annotation revealed between 2,465 and 2,576 protein-coding genes per genome, averaging 2,537 genes. Core-genome phylogeny, gene flow estimates, and overall gene content divergence consistently supported the within-species divergence into two major populations. While isolation by distance partially explained the within-population divergence, the factors driving divergence between populations remain unclear. Nevertheless, this species likely has a closed pan-genome comprising approximately 3,030 genes, with our sampling providing sufficient coverage of its genomic diversity. To investigate the divergence and potential adaptations, we identified genomic regions with significantly lower nucleotide diversity, indicating loci that may have undergone selective sweeps within each population. We identified 149 and 289 genes within these regions in populations A and B, respectively. Only 16 genes were common to both populations, suggesting that selective sweeps primarily targeted different genes in the two populations. Key genes related to functions such as carbon fixation, photosynthesis, motility, and ion transport were highlighted. ConclusionsThis work provides a population genomics perspective on a hot spring cyanobacterial species in Taiwan. Beyond advancing our understanding of microbial genomics and evolution, the strains collected and genome sequences generated in this work provide valuable materials for future development and utilization of biological resources.

genomics↗

bioRxiv2023

Vascular oxidative stress causes neutrophil arrest in brain capillaries, leading to decreased cerebral blood flow and contributing to memory impairment in a mouse model of Alzheimer's disease

INTRODUCTIONIn this study, we explore the role of oxidative stress produced by NOX2-containing NADPH oxidase as a molecular mechanism causing capillary stalling and cerebral blood flow deficits in the APP/PS1 mouse model of AD. METHODSWe inhibited NOX2 in APP/PS1 mice by administering a 10 mg/kg dose of the peptide inhibitor gp91-ds-tat i.p., for two weeks. We used in vivo two-photon imaging to measure capillary stalling, penetrating arteriole flow, and vascular inflammation. We also characterized short-term memory function and gene expression changes in cerebral microvessels. RESULTSWe found that after NOX2 inhibition capillary stalling, as well as parenchymal and vascular inflammation, were significantly reduced. In addition, we found a significant increase in penetrating arteriole flow, followed by an improvement in short-term memory, and downregulation of inflammatory gene expression pathways. DISCUSSIONOxidative stress is a major mechanism leading to microvascular dysfunction in AD, and represents an important therapeutic target.

neuroscience↗

bioRxiv2022

Protein N-Terminomics Reveals Major Proteases in Regulating Beige Adipocyte Differentiation

In this comprehensive study, we present an innovative analytical platform designed to capture the temporal shifts in both the proteome and protein N-terminome during beige adipocyte differentiation. Employing a refined N-terminomics technique, we achieved a high purity of 97% in isolating protein N-terminal peptides. Our data encompassed 7,171 unique N-terminal peptides, with 3,043 from canonical proteins and 4,129 with neo-N-termini. Strikingly, nearly half (44%) of the proteins revealed distinct temporal trajectories between the global proteome and the N-terminome. This underscores the central role of proteolysis in beige adipocyte differentiation. Experimentally, knockdown of either Pmpcb, Plg, or Cstd in preadipocytes attenuated thermogenesis, manifested by reduced levels of beige adipocyte markers like Cidea, Pgc1a, Ucp1, and Tbx1 and an increase in adipogenic proteins, thereby hampering beige adipocyte maturation. A salient discovery was the non-apoptotic role of caspase 8 protease; inhibiting its proteolytic action amplified Ucp1 expression levels. Collectively, our findings spotlight proteases and their proteolytic by-products as vital regulators in beige adipocyte differentiation.

cell biology↗

bioRxiv2021

Skopi: a simulation package for diffractive imaging of noncrystalline biomolecules

X-ray free electron lasers (XFEL) have the ability to produce ultra-bright femtosecond X-ray pulses for coherent diffraction imaging of biomolecules. While the development of methods and algorithms for macromolecular crystallography is now mature, XFEL experiments involving aerosolized or solvated biomolecular samples offer new challenges both in terms of experimental design and data processing. Skopi is a simulation package that can generate single-hit diffraction images for reconstruction algorithms, multi-hit diffraction images of aggregated particles for training machine learning classification tasks using labeled data, diffraction images of randomly distributed particles for fluctuation X-ray scattering (FXS) algorithms, and diffraction images of reference and target particles for holographic reconstruction algorithms. We envision skopi as a resource to aid the development of on-the-fly feedback during non-crystalline experiments at XFEL facilities, which will provide critical insights into biomolecular structure and function.

biophysics↗

bioRxiv2020

CyDAP-A fluorescent probe for cytosolic dopamine detection

Dopamine (DA) is an essential neurotransmitter modulating motor and cognitive functions. Several neurological disorders, including Parkinsons disease (PD) and drug addiction, are the result of DA system dysfunction; however, it remains incomplete understood of why DA neuron is selectively more vulnerable than other neurons. Here we utilize the spectral feature of human MAO B (monoamine oxidase B) to design a genetic-amenable, GFP-based fluorescent probe CyDAP. Upon genetic and pharmacological manipulations to elevate the cytosolic DA levels in cells and Drosophila models, CyDAP shows enhanced GFP emission, suggesting this probe is feasible for DA detection. Furthermore, we observe that expressing human -Synuclein in Drosophila elicited GFP emission from CyDAP, suggesting a link between cytosolic DA imbalance and regional vulnerability in PD context. Importantly, CyDAP can detect the change of cytosolic DA in live Drosophila brains, as demonstrated by time-lapse and the 4D light-sheet confocal recording. CyDAP may serve as a tool for evaluating metabolic deregulation of DA in brain models of PD and other DA system-related psychiatric disorders.

neuroscience↗

bioRxiv2020

Isolation of protein N-terminal peptides by charge-mediated position- elective enrichment using strong cation exchange chromatography

We developed a simple and rapid method to enrich protein N-terminal peptides, in which the protease TrypN is first employed to generate protein N-terminal peptides without Lys or Arg and internal peptides with two positive charges at their N-termini, and then the N-terminal peptides are separated from the internal peptides by means of CHArge-Mediated Position-selective (CHAMP) enrichment using strong cation exchange (SCX) chromatography. This CHAMP-SCX approach was applied to 20 g of human HEK293T cell lysate proteins to profile the N-terminal proteome. On average, 1,550 acetylated and 200 unmodified protein N-terminal peptides were successfully identified in a single LC/MS/MS run with less than 3% contamination with internal peptides, even when we accepted only canonical protein N-termini registered in the Swiss-Prot database. Since this method involves only two steps, protein digestion and chromatographic separation, without the need for tedious chemical reactions, it should be useful for comprehensive profiling of protein N-termini, including proteoforms with neo-N-termini.

cell biology↗

bioRxiv2019

Coordination between stabilizing circuits and updating circuits in spatial orientation working memory

Spatial orientation memory plays a crucial role in animal navigation. Recent studies of tethered Drosophila melanogaster (fruit fly) in a virtual reality setting showed that the head direction is encoded in the form of an activity bump, i.e. localized neural activity, in the torus-shaped ellipsoid body (EB). However, how this system is involved in orientation working memory is not well understood. We investigated this question using free moving flies (Drosophila melanogaster) in a spatial orientation memory task by manipulating two EB subsystems, C and P circuits, which are hypothesized for stabilizing and updating the activity bump, respectively. To this end, we suppressed or activated two types of inhibitory ring neurons (EIP and P) which innervate EB, and we discovered that manipulating the two inhibitory neuron types produced distinct behavioral deficits, suggesting specific roles of the inhibitory neurons in coordinating the stabilization and updating functions of the EB circuits. We further elucidate the neural mechanisms underlying such control circuits using a connectome-constrained spiking neural network model. Significance statementHead-direction (HD) system has been discovered in rodents for decades. But the detailed neural circuit mechanisms underlying the HD system were only described recently by studies of fruit flies on the similar HD system. However, how this fruit fly HD system involves in orientation memory was not well investigated. The present study addresses this question by investigating free moving flies in a spatial orientation working memory task. By combining neural functional experiments and neural circuit modelling, the study shows how disrupting either of the two subcircuits, one stabilizing and the other updating the neural activity, in the HD system leads to different behavioral impairments. The result suggests specific roles of the HD subcircuits in the spatial orientation working memory. Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/819185v2_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@101cb04org.highwire.dtl.DTLVardef@b7ac8borg.highwire.dtl.DTLVardef@a10a41org.highwire.dtl.DTLVardef@a8691e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2019

Structural Lipidomics and Molecular Imaging of C=C Positional Isomers Enabled by mCPBA Epoxidation with Tandem Mass Spectrometry

Cellular lipidome is highly regulated through lipogenesis, rendering diverse double-bond positional isomers (C=C isomer) of a given unsaturated lipid species. In recent years, there are increasing reports indicating the physiological roles of C=C isomer compositions associated with diseases, while the biochemistry has not been fully understood due to the challenge in characterizing lipid isomers inherent to conventional mass spectrometry-based lipidomics. To address this challenge, we reported a universal, user-friendly, derivatization-based strategy, MELDI (mCPBA Epoxidation for Lipid Double-bond Identification), which enables both large-scale identification and spatial mapping of biological C=C isomers using commercial mass spectrometers without any instrument modification. With the developed liquid-chromatography mass spectrometry (LC-MS) lipidomics workflow, we elucidated more than 100 isomers among mono- and poly-unsaturated fatty acids and glycerophospholipids in both human serum, where novel isomers of low abundance were unambiguously quantified for the first time. The capability of MELDI-LC-MS in lipidome analysis was further demonstrated using the differentiated 3T3-L1 adipocytes, providing an insight into the cellular lipid reprogramming upon stearoyl-coenzyme A desaturase 1 (SCD1) inhibition. Finally, we highlighted the versatility of MELDI coupled with mass spectrometry imaging to spatially resolve cancer-associated alteration of lipid isomers in a metastatic mouse tissue section. Our results suggested that MELDI will contribute to current lipidomics pipelines with a deeper level of structural information, allowing us to investigate underlying lipid biochemistry.

biochemistry↗

bioRxiv2019

Dominant coral bacterium Endozoicomonas acroporae metabolizes DMSP

Dominant coral-associated Endozoicomonas bacteria species are hypothesized to play a role in the coral-sulfur cycle by metabolizing Dimethylsulfoniopropionate (DMSP) into Dimethylsulfide (DMS); however, no sequenced genome to date harbors genes for this process. In this study, we assembled high-quality (>95% complete) genomes of strains of a recently added species Endozoicomonas acroporae (Acr-14T, Acr-1 and Acr-5) isolated from the coral Acropora muricata and performed comparative genomic analysis on genus Endozoicomonas. We identified the first DMSP CoA-transferase/lyase--a dddD gene homolog found in all E. acroporae strains--and functionally characterized bacteria capable of metabolizing DMSP into DMS via the DddD cleavage pathway using RT-qPCR and gas chromatography (GC). Furthermore, we demonstrated that E. acroporae strains can use DMSP as the sole carbon source and have genes arranged in an operon-like manner to link DMSP metabolism to the central carbon cycle. This study confirms the role of Endozoicomonas in the coral sulfur cycle.

ecology↗

bioRxiv2018

Targeting BMI1 and MCL1 for Lung Adenocarcinoma Treatment

Lung cancer is the leading cause of cancer-associated death worldwide. Early metastasis and the recurrence remain major challenges for lung cancer treatment in clinic. Targeting the cancer stemness could be a potential strategy to restrain tumor progression. In the current study, we found that in lung adenocarcinoma (LAC), BMI1 and MCL1 play crucial roles in invasion, chemo-resistance, and tumor initiation. JNK signaling is a link between oncogenic pathway or environment stress to cancer stemness. The activation of JNK, either by EGFR or chemotherapy agent, stabilized BMI1 and MCL1 proteins through suppressing the expression of E3-ubiquitin ligase HUWE1. In lung cancer patient samples, high level of BMI1 is correlated with poor survival, and the expression of BMI1 is positively correlated with MCL1. A novel small-molecule BI-44 was synthesized, which effectively suppressed BMI1/MCL1 expression and inhibited tumor formation and progression in preclinical models. Targeting BMI1/MCL1 provides the basis for a new therapeutic approach in the treatment of LAC.

cancer biology↗