Oncogenesis最新文献

The serine/glycine (ser/gly) synthesis pathway branches from glycolysis and is hyperactivated in approximately 30% of cancers. In ~13% of glioblastoma cases, we observed frequent amplifications and rare mutations in the gene encoding the enzyme PSPH, which catalyzes the last step in the synthesis of serine. This urged us to unveil the relevance of PSPH genetic alterations and subsequent ser/gly metabolism deregulation in the pathogenesis of glioblastoma. Primary glioblastoma cells overexpressing PSPH and PSPH^V116I showed an increased clonogenic capacity, cell proliferation, and migration, supported by elevated nucleotide synthesis and utilization of reductive NAD(P). We previously identified sertraline as an inhibitor of ser/gly synthesis and explored its efficacy at suboptimal dosages in combination with the clinically pretested chloroquine to target ser/gly^high glioblastoma models. Interestingly, ser/gly^high glioblastomas, including PSPH^amp and PSPH^V116I, displayed selective synergistic inhibition of proliferation in response to combination therapy. PSPH knockdown severely affected ser/gly^high glioblastoma clonogenicity and proliferation, while simultaneously increasing its sensitivity to chloroquine treatment. Metabolite landscaping revealed that sertraline/chloroquine combination treatment blocks NADH and ATP generation and restricts nucleotide synthesis, thereby inhibiting glioblastoma proliferation. Our previous studies highlight ser/gly^high cancer cell modulation of its microenvironment at the level of immune suppression. To this end, high PSPH expression predicts poor immune checkpoint therapy responses in glioblastoma patients. Interestingly, we show that PSPH amplifications in glioblastoma facilitate the expression of immune suppressor galectin-1, which can be inhibited by sertraline treatment. Collectively, we revealed that ser/gly^high glioblastomas are characterized by enhanced clonogenicity, migration, and suppression of the immune system, which could be tackled using combined sertraline/chloroquine treatment, revealing novel therapeutic opportunities for this subgroup of GBM patients.

SS18-SSX onco-fusion protein formed through aberrant chromosomal translocation t (X, 18; p11, q11), is the hallmark and plays a critical role in synovial sarcomagenesis. The recent works indicated that both the pathological SS18-SSX tumorigenic fusion and the corresponding intrinsic physiological SS18 protein can form condensates but appear to have disparate properties. The underlying regulatory mechanism and the consequent biological significance remain largely unknown. We show that the physical properties of oncogenic fusion protein SS18-SSX condensates within cells undergo alterations compared to the proto-oncogene protein SS18. By small-molecule screening and mutant assay, we identified the recognition of H2AK119ub histone modification could account for the distinctive properties of SS18-SSX1 condensates. Notably, we show that SS18-SSX1 condensates have impact on SS18 condensates and hijack that in a phase separation manner, resulting in the relocation of protein SS18 to the H2AK119ub modification targeted by SS18-SSX1. Consequently, this leads to the downregulation of tumor suppressor genes occupied by SS18 physiologically, like CAV1 and DAB2. These results reveal the underlying mechanism of genomic disorder and tumorigenesis caused by the remodeling of oncoprotein SS18-SSX1 condensates at the macroscopic level.

Although there have been advances in understanding colorectal cancer (CRC) pathogenesis, significant gaps still exist, highlighting the need for deeper insights. Dysregulated protein homeostasis, including perturbations in the epidermal growth factor receptor (EGFR) pathway, remains a focal point in CRC pathogenesis. Within this context, the roles of ubiquitin ligases and deubiquitinases have attracted attention, but exploration of their precise contributions is still in its early stages. To address this gap, we investigated the involvement of the deubiquitinase USP10 in CRC. Our in vitro and in vivo study reveals a new paradigm in CRC biology and unravels a novel mechanistic axis, demonstrating for the first time the involvement of inositol polyphosphate 4-phosphatase type II B (INPP4B) in USP10-mediated CRC modulation. Specifically, our study demonstrates that the loss of USP10 results in reduced sensitivity to the EGFR tyrosine kinase inhibitors gefitinib and osimertinib. This is accompanied by a decrease in the activation of the AKT1/PKB pathway upon EGF stimulation, which is mediated by INPP4B. Importantly, in vivo xenograft experiments validate these findings and highlight the crucial role of USP10, particularly in conjunction with INPP4B, in driving CRC progression. The findings enhance our understanding of CRC pathobiology and reveal a new regulatory axis involving USP10 and INPP4B in CRC progression. This unique insight identifies USP10 and INPP4B as potential therapeutic targets in CRC.

Immunotherapy has revolutionized cancer treatment, but the lack of a reliable predictive biomarker for treatment response remains a challenge. Alpha-1,6-Mannosylglycoprotein 6-β-N-Acetylglucosaminyltransferase 5 (MGAT5) is a key regulator of complex N-glycan synthesis, and its dysregulation is associated with cancer progression. The lectin Phaseolus vulgaris leukoagglutinin (PHA-L) specifically binds to mature MGAT5 products. Previous studies have indicated elevated PHA-L staining in head and neck squamous cell carcinoma (HNSCC), which implies increased activity of MGAT5. However, the specific role of MGAT5 in HNSCC remains unclear. In this study, we found significantly higher PHA-L staining and MGAT5 expression in HNSCC tumors compared to adjacent non-tumor tissues. Using a mass spectrometry (MS)-based glycoproteomic approach, we identified 163 potential protein substrates of MGAT5. Functional analysis revealed that protein substrates of MGAT5 regulated pathways related to T cell proliferation and activation. We further discovered that PD-L1 was among the protein substrates of MGAT5, and the expression of MGAT5 protected tumor cells from cytotoxic T lymphocyte (CTL) killing. Treatment of nivolumab alleviated the protective effects of MGAT5 on CTL activity. Consistently, patients with MGAT5-positive tumors showed improved responses to immunotherapy compared to those with MGAT5-negative tumors. Using purified PD-L1 from HNSCC cells and a glycoproteomic approach, we further deciphered that the N35 and N200 sites carry the majority of complex N-glycans on PD-L1. Our findings highlight the critical role of MGAT5-mediated branched N-glycans on PD-L1 in modulating the interaction with the immune checkpoint receptor PD-1. Consequently, we propose that MGAT5 could serve as a biomarker to predict patients' responses to anti-PD-1 therapy. Furthermore, targeting the branched N-glycans at N35 and N200 of PD-L1 may lead to the development of novel diagnostic and therapeutic approaches.

The activation of nuclear factor erythroid 2-related factor 2 (NRF2) has been observed in various cancers. Yet its exact contribution to the development of head and neck squamous cell carcinoma (HNSCC) remains undetermined. We previously found that NRF2 signaling is critical for the differentiation of squamous basal progenitor cells, while disruption of NRF2 causes basal cell hyperplasia. In this study, we revealed a correlation between elevated NRF2 activity and poor outcomes in HNSCC patients. We demonstrated that NRF2 facilitates tumor proliferation, migration, and invasion, as evidenced by both in vitro and in vivo studies. Significantly, NRF2 augments the expression of the antioxidant enzyme GPX2, thereby enhancing the proliferative, migratory, and invasive properties of HNSCC cells. Activation of GPX2 is critical for sustaining cancer stem cells (CSCs) by up-regulating NOTCH3, a key driver of cancer progression. These results elucidate that NRF2 regulates HNSCC progression through the NRF2-GPX2-NOTCH3 axis. Our findings proposed that pharmacological targeting of the NRF2-GPX2-NOTCH3 axis could be a potential therapeutic approach against HNSCC.

Oxaliplatin is effective against colorectal cancer (CRC), but resistance hampers treatment. We found upregulated Dickkopf-1 (DKK1, a secreted protein) in oxaliplatin-resistant (OR) CRC cell lines and DKK1 levels increased by more than 2-fold in approximately 50% of oxaliplatin-resistant CRC tumors. DKK1 activates AKT via cytoskeleton-associated protein 4 (CKAP4, a DKK1 receptor), modulating oxaliplatin responses in vitro and in vivo. The leucine zipper (LZ) domain of CKAP4 and cysteine-rich domain 1 (CRD1) of secreted DKK1 are crucial for their interaction and AKT signaling. By utilizing the LZ protein, we disrupted DKK1 signaling, enhancing oxaliplatin sensitivity in OR CRC cells and xenograft tumors. This suggests that DKK1 as a chemoresistant factor in CRC via AKT activation. Targeting DKK1 with the LZ protein offers a promising therapeutic strategy for oxaliplatin-resistant CRC with high DKK1 levels. This study sheds light on oxaliplatin resistance mechanisms and proposes an innovative intervention for managing this challenge.

Hepatocellular carcinoma (HCC) is a prevalent and aggressive malignancy associated with high risks of recurrence and metastasis. Liver cancer stem cells (CSCs) are increasingly recognized as pivotal drivers of these processes. In our previous research, we demonstrated the involvement of TFCP2L1 in maintaining the pluripotency of embryonic stem cells. However, its relevance to liver CSCs remains unexplored. In this study, we report an inverse correlation between TFCP2L1 protein levels in HCC tissue and patient outcomes. The knockdown of TFCP2L1 significantly reduced HCC cell proliferation, invasion, metastasis, clonal formation, and sphere-forming capacity, while its overexpression enhanced these functions. In addition, experiments using a nude mouse model confirmed TFCP2L1’s essential role in liver CSCs’ function and tumorigenic potential. Mechanistically, we showed that TFCP2L1 promotes the stemness of CSCs by upregulating NANOG, which subsequently activates the JAK/STAT3 pathway, thereby contributing to HCC pathogenesis. Importantly, we identified a specific small molecule targeting TFCP2L1’s active domain, which, in combination with Sorafenib, sensitizes hepatoma cells to treatment. Together, these findings underscore TFCP2L1’s pathological significance in HCC progression, supporting its potential as a prognostic biomarker and therapeutic target in this disease.

BAP1, BRCA1-Associated Protein 1, serves as a novel tumor suppressor through the deubiquitination of monoubiquitination of H2A and subsequent gene transcriptional regulation. Regulated cell death like apoptosis or ferroptosis is considered an essential mechanism mediating tumor suppression. Previous reports, including ours, have demonstrated that BAP1 could promote apoptosis and ferroptosis to inhibit tumor development. Whether BAP1 regulated additional types of cell death remains unclear. Disulfidptosis is a recently identified novel cell death mode characterized by aberrant accumulation of intracellular disulfide (e.g., cystine) and depletion of NADPH. In this study, we first demonstrated that BAP1 could significantly protect disulfidptosis induced by glucose starvation, which is validated by various cell death inhibitors and the accumulation of disulfide bonds in the cytoskeleton proteins. BAP1 is known to inhibit SLC7A11 expression. We found that the protective effect of BAP1 against disulfidptosis was counteracted when overexpressing SLC7A11 or adding additional cystine. Conversely, BAP1-mediated suppression of disulfidptosis was largely abrogated when SLC7A11-mediated cystine uptake was inhibited by the knockout of SLC7A11 or erastin treatment. Besides, high BAP1 expression showed lower NADP⁺/NADPH levels, which might confer resistance to disulfidptosis. Consistent with these observations, the expression level of BAP1 was also positively correlated with NADPH-related genes in KIRC patients, though the underlying mechanism mediating NADPH regulation remains further investigation. In summary, our results revealed the role of BAP1 in the regulation disulfidptosis and provided new insights into the understanding of disulfidptosis in tumor development.

Neratinib is a tyrosine kinase inhibitor that is used for the therapy of patients with HER2+ breast tumors. However, despite its clinical benefit, resistance to the drug may arise. Here we have created cellular models of neratinib resistance to investigate the mechanisms underlying such resistance. Chronic neratinib exposure of BT474 human HER2+ breast cancer cells resulted in the selection of several clones resistant to the antiproliferative action of the drug. The clones were characterized biochemically and biologically using a variety of techniques. These clones retained HER2 levels similar to parental cells. Knockdown experiments showed that the neratinib-resistant clones retained oncogenic dependence on HER2. Moreover, the tyrosine phosphorylation status of BT474 and the resistant clones was equally sensitive to neratinib. Transcriptomic and Western analyses showed that peptidylarginine deiminase 3 was overexpressed in the three neratinib-resistant clones studied but was undetectable in BT474 cells. Experiments performed in the neratinib-resistant clones showed that reduction of PADI3 or inhibition of its function restored sensitivity to the antiproliferative action of neratinib. Moreover, overexpression of FLAG-tagged PADI3 in BT474 cells provoked resistance to the antiproliferative action of neratinib. Together, these results uncover a role of PADI3 in the regulation of sensitivity to neratinib in breast cancer cells overexpressing HER2 and open the possibility of using PADI3 inhibitors to fight resistance to neratinib.