Publications by authors named "Gongwei Wu"

Anti-CD38 monoclonal antibodies like Daratumumab (Dara) are effective in multiple myeloma (MM); however, drug resistance ultimately occurs and the mechanisms behind this are poorly understood. Here, we identify, via two in vitro genome-wide CRISPR screens probing Daratumumab resistance, KDM6A as an important regulator of sensitivity to Daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Loss of KDM6A leads to increased levels of H3K27me3 on the promoter of CD38, resulting in a marked downregulation in CD38 expression, which may cause resistance to Daratumumab-mediated ADCC.

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Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas.

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Recent advances in single-cell epigenomic techniques have created a growing demand for scATAC-seq analysis. One key analysis task is to determine cell type identity based on the epigenetic data. We introduce scATAnno, a python package designed to automatically annotate scATAC-seq data using large-scale scATAC-seq reference atlases.

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PROteolysis TArgeting Chimeras (PROTACs) are an emerging class of promising therapeutic modalities that selectively degrade intracellular proteins of interest by hijacking the ubiquitin-proteasome system. However, the lack of techniques to efficiently transport these degraders to targeted cells and consequently the potential toxicity of PROTACs limit their clinical applications. Here, a strategy of nanoengineered PROTACs, that is, Nano-PROTACs, is reported, which improves the bioavailability of PROTACs and maximizes their capacity to therapeutically degrade intracellular oncogenic proteins for tumor therapy.

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Interleukin (IL)-2-inducible T cell kinase (ITK) is essential for T cell receptor (TCR) signaling and plays an integral role in T cell proliferation and differentiation. Unlike the ITK homolog BTK, no inhibitors of ITK are currently US Food and Drug Administration (FDA) approved. In addition, recent studies have identified mutations within BTK that confer resistance to both covalent and non-covalent inhibitors.

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Article Synopsis
  • Lysine-specific demethylase 6A (KDM6A) is often mutated in bladder cancer and is considered a tumor suppressor, but its therapeutic role in metastasis is still unclear.
  • A novel mucoadhesive messenger RNA (mRNA) nanoparticle strategy is developed for effective delivery of KDM6A mRNA directly to bladder tumors in mice, enhancing mRNA exposure and expression duration.
  • This method not only shows promise for treating bladder cancer metastasis but also works well in combination with other cancer therapies, potentially improving overall treatment outcomes.
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Immunomodulatory (IMiD) agents like lenalidomide and pomalidomide induce the recruitment of IKZF1 and other targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and degradation. These agents are highly active in B-cell lymphomas and a subset of myeloid diseases but have compromised effects in T-cell lymphomas (TCLs). Here, we show that 2 factors determine resistance to IMiDs among TCLs.

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RNA interference (RNAi) is a powerful approach in the treatment of various diseases including cancers. The clinical translation of small interfering RNA (siRNA)-based therapy requires safe and efficient delivery vehicles. Here, we report a siRNA nanogels (NG)-based delivery vehicle, which is driven directly by the intercalation between nucleic acid bis-intercalator and siRNA molecules.

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Article Synopsis
  • Arsenical drugs have been effective in treating acute promyelocytic leukemia, but using them for solid tumors faces challenges due to their toxicity versus effectiveness.
  • Researchers developed PEGylated arsenene nanodots (AsNDs@PEG) that can specifically target and kill solid tumor cells by inducing oxidative stress, leading to severe cellular damage.
  • Combining AsNDs@PEG with the plant-derived anticancer drug β-elemene shows enhanced antitumor effects, and their safe fabrication presents a promising new treatment option for solid tumors with minimal side effects.
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A hallmark of acute myeloid leukemia (AML) is the inability of self-renewing malignant cells to mature into a non-dividing terminally differentiated state. This differentiation block has been linked to dysregulation of multiple cellular processes, including transcriptional, chromatin, and metabolic regulation. The transcription factor HOXA9 and the histone demethylase LSD1 are examples of such regulators that promote differentiation blockade in AML.

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The MYC oncoprotein activates and represses gene expression in a transcription-dependent or transcription-independent manner. Modification of mRNA emerges as a key gene expression regulatory nexus. We sought to determine whether MYC alters mRNA modifications and report here that MYC promotes cancer progression by down-regulating N6-methyladenosine (m A) preferentially in transcripts of a subset of MYC-repressed genes (MRGs).

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Metastasis is responsible for the majority of breast cancer-related deaths, however, the mechanisms underlying metastasis in this disease remain largely elusive. Here we report that under hypoxic conditions, alternative splicing of MBD2 is suppressed, favoring the production of MBD2a, which facilitates breast cancer metastasis. Specifically, MBD2a promoted, whereas its lesser known short form MBD2c suppressed metastasis.

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The transcriptional role of cMyc (or Myc) in tumorigenesis is well appreciated; however, it remains to be fully established how extensively Myc is involved in the epigenetic regulation of gene expression. Here, we show that by deactivating succinate dehydrogenase complex subunit A (SDHA) via acetylation, Myc triggers a regulatory cascade in cancer cells that leads to H3K4me3 activation and gene expression. We find that Myc facilitates the acetylation-dependent deactivation of SDHA by activating the SKP2-mediated degradation of SIRT3 deacetylase.

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Menin is an enigmatic protein that displays unique ability to either suppress or promote tumorigenesis in a context-dependent manner. The role for Menin to promote oncogenic functions has been largely attributed to its essential role in forming the MLL methyltransferase complex, which mediates H3K4me3. Here, we identify an unexpected role of Menin in enhancing the transactivity of oncogene MYC in a way independent of H3K4me3 activity.

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Cancer progression depends on cellular metabolic reprogramming as both direct and indirect consequence of oncogenic lesions; however, the underlying mechanisms are still poorly understood. Here, we report that CUEDC2 (CUE domain-containing protein 2) plays a vital role in facilitating aerobic glycolysis, or Warburg effect, in cancer cells. Mechanistically, we show that CUEDC2 upregulates the two key glycolytic proteins GLUT3 and LDHA via interacting with the glucocorticoid receptor (GR) or 14-3-3ζ, respectively.

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Cancer cells are known for their capacity to rewire metabolic pathways to support survival and proliferation under various stress conditions. Ketone bodies, though produced in the liver, are not consumed in normal adult liver cells. We find here that ketone catabolism or ketolysis is re-activated in hepatocellular carcinoma (HCC) cells under nutrition deprivation conditions.

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Cancer cells are known to undergo metabolic reprogramming to sustain survival and rapid proliferation, however, it remains to be fully elucidated how oncogenic lesions coordinate the metabolic switch under various stressed conditions. Here we show that deprivation of glucose or glutamine, two major nutrition sources for cancer cells, dramatically activated serine biosynthesis pathway (SSP) that was accompanied by elevated cMyc expression. We further identified that cMyc stimulated SSP activation by transcriptionally upregulating expression of multiple SSP enzymes.

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Aberrant expression of Lin28 and let-7 has been observed in many human malignancies. However, its functions and underlying mechanisms remain largely elusive. Here we show that aberrant expression of Lin28 and let-7 facilitates aerobic glycolysis, or Warburg effect, in cancer cells.

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LKB1 loss-of-function mutations, observed in ∼30% of human lung adenocarcinomas, contribute significantly to lung cancer malignancy progression. We show that lysyl oxidase (LOX), negatively regulated by LKB1 through mTOR-HIF-1α signaling axis, mediates lung cancer progression. Inhibition of LOX activity dramatically alleviates lung cancer malignancy progression.

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