Shuzhong Yao

METAP2 inhibits K48-linked ubiquitination of YTHDF2 to promote ovarian cancer progression

A noncanonical role of SAT1 enables anchorage independence and peritoneal metastasis in ovarian cancer

Anchorage-independent survival of ovarian tumor cells in ascites is the initial and critical step for peritoneal metastasis. How ovarian tumor cells achieve anchorage independence remains unclear. Here we show that a noncanonical role of spermidine/spermine N1-acetyltransferase 1 (SAT1) dictates anchorage-independent cell survival and potentiates metastatic dissemination in ovarian cancer. SAT1-high cancer cells are prevalent in ascitic tumors, and high SAT1 expression in primary tumors is linked to increased peritoneal metastasis rates in ovarian cancer patients. Mechanistically, SAT1 noncanonically acetylates H3K27 domains in multiple mitosis-regulating genes, increasing their transcriptional levels and protecting disseminating cells from aberrant mitosis and mitotic cell death. Notably, the acetylation of H3K27 by SAT1 depends on the reductive carboxylation of glutamine to supply acetyl-CoA in the nucleus. SAT1 inhibition with the small-molecule inhibitor ginkgolide B attenuates the metastatic tumor burden in mouse models. We conclude that SAT1 inhibition is a promising therapeutic strategy for metastatic ovarian cancer.

Cuproptosis inhibits tumor progression and enhances cisplatin toxicity in ovarian cancer

Abstract Cuproptosis is a novel form of regulated cell death triggered by copper ion and copper ionophore. While cuproptosis has been actively explored as a potential target for cancer therapy, its role in ovarian cancer (OC) still remains unclear. In this study, we demonstrate that cuproptosis inhibits OC cell proliferation, migration, and invasion through FDX1 regulation and suppresses tumor growth in a mouse model. We also confirm that cuproptosis enhances OC sensitivity to cisplatin treatment both in vivo and in vitro. Moreover, our findings reveal that cuproptosis affects cholesterol biosynthesis in OC cells, with cholesterol playing a crucial role in its cytotoxic effect. Taken together, our results elucidate the effect of cuproptosis in OC and suggest it as a promising therapeutic strategy.

HNRNPC mediates lymphatic metastasis of cervical cancer through m6A-dependent alternative splicing of FOXM1

AbstractCervical cancer (CCa) patients with lymph node (LN) metastasis face poor prognoses and have limited treatment options. Aberrant N6-methyladenosine (m6A) modification of RNAs are known to promote tumor metastasis, but their role in CCa remains unclear. Our study reveals that HNRNPC, an alternative splicing (AS) factor and m6A reader, increases tumor-related variants through m6A-dependent manner, thereby promoting lymphatic metastasis in CCa. We found that HNRNPC overexpression correlates with lymphatic metastasis and poorer prognoses in CCa patients. Functionally, knocking down HNRNPC markedly inhibited the migration and invasion of several CCa cell lines, while supplementing HNRNPC restored the malignant phenotypes of these cells. Mechanistically, HNRNPC regulates exon skipping of FOXM1 by binding to its m6A-modified motif. Mutating the m6A site on FOXM1 weakened the interaction between HNRNPC and FOXM1 pre-RNA, leading to a reduction in the metastasis-related FOXM1-S variant. In conclusion, our findings demonstrate that m6A-dependent alternative splicing mediated by HNRNPC is essential for lymphatic metastasis in CCa, potentially providing novel clinical markers and therapeutic strategies for patients with advanced CCa.

LNMAC Promotes Cervical Squamous Cell Carcinoma Lymphatic Metastasis via Epigenetic Regulation of FGF2‐Induced Lymphangiogenesis

AbstractThe lymph node is the most common site of distant metastasis of cervical squamous cell carcinoma (CSCC), which elicits dismal prognosis and limited efficiency for treatment. Elucidation of the mechanisms underlying CSCC lymphatic metastasis would provide potential therapeutic strategies for nodal metastatic of CSCC. Here, based on in vivo lymphatic metastasis screening model, a circular RNA is identified that is termed as lymph node metastasis associated circRNA (LNMAC), is markedly upregulated in lymphatic metastatic CSCC and correlated with lymph node metastasis. Overexpression of LNMAC dramatically augments the metastatic capability of CSCC cells to the lymph node via inducing lymphangiogenesis. Mechanistically, LNMAC epigenetically upregulates fibroblast growth factor 2 (FGF2) expression by directly associating with histone acacetylase 1 (HDAC1), preventing Importin α6/8‐mediated nuclear translocation of HDAC1 and eliciting histone H3K27ac‐induced FGF2 transcriptional activation. Treatment with 3F12E7, an anti‐FGF2 monoclonal antibody, effectively inhibits LNMAC‐induced CSCC lymphatic metastasis. Taken together, these findings indicate that LNMAC plays a crucial role in FGF2‐mediated lymphangiogenesis and lymphatic metastasis, highlighting that LNMAC might be a therapeutic target for lymph node metastasis in CSCC patients.

CircMAST1 inhibits cervical cancer progression by hindering the N4-acetylcytidine modification of YAP mRNA

Abstract Background Cervical cancer (CCa) is the fourth most common cancer among females, with high incidence and mortality rates. Circular RNAs (circRNAs) are key regulators of various biological processes in cancer. However, the biological role of circRNAs in cervical cancer (CCa) remains largely unknown. This study aimed to elucidate the role of circMAST1 in CCa. Methods CircRNAs related to CCa progression were identified via a circRNA microarray. The relationship between circMAST1 levels and clinicopathological features of CCa was evaluated using the clinical specimens and data of 131 patients with CCa. In vivo and in vitro experiments, including xenograft animal models, cell proliferation assay, transwell assay, RNA pull-down assay, whole-transcriptome sequencing, RIP assay, and RNA-FISH, were performed to investigate the effects of circMAST1 on the malignant behavior of CCa. Results CircMAST1 was significantly downregulated in CCa tissues, and low expression of CircMAST1 was correlated with a poor prognosis. Moreover, our results demonstrated that circMAST1 inhibited tumor growth and lymph node metastasis of CCa. Mechanistically, circMAST1 competitively sequestered N-acetyltransferase 10 (NAT10) and hindered Yes-associated protein (YAP) mRNA ac4C modification to promote its degradation and inhibit tumor progression in CCa. Conclusions CircMAST1 plays a major suppressive role in the tumor growth and metastasis of CCa. In particular, circMAST1 can serve as a potential biomarker and novel target for CCa.

Primary high-grade serous cancer arising from uterosacral ligament endometriosis: two case reports

Although high-grade serous cancer (HGSC) accounts for >70% of ovarian epithelial cancers, it is rarely associated with endometriosis. No previous study has reported an association between the malignant transformation of uterine ligament endometriosis and HGSC. Here, we reported two cases of Chinese female patients with HGSC arising from endometriosis in the uterosacral ligament. They had a long-term history of endometriosis and dysmenorrhea. Both were diagnosed with HGSC at stage IIB. They underwent operations and six cycles of chemotherapy with paclitaxel and carboplatin and have remained disease-free to date. Genomic analysis showed no known/suspected pathogenic variations or somatic homologous recombination deficiency in the two cases. In conclusion, these rare cases of HGSC from endometriosis might indicate a new origin of ovarian type II carcinoma. Patients with a long-term history of endometriosis and sudden aggravation of dysmenorrhea or vaginal bleeding should be aware of the possibility of endometriotic malignant transformation.

ROS-regulated phosphorylation of ITPKB by CAMK2G drives cisplatin resistance in ovarian cancer

Platinum resistance accounts for much of the high mortality and morbidity associated with ovarian cancer. Identification of targets with significant clinical translational potential remains an unmet challenge. Through a high-throughput synthetical lethal screening for clinically relevant targets using 290 kinase inhibitors, we identify calcium/calmodulin-dependent protein kinase II gamma (CAMK2G) as a critical vulnerability in cisplatin-resistant ovarian cancer cells. Pharmacologic inhibition of CAMK2G significantly sensitizes ovarian cancer cells to cisplatin treatment in vitro and in vivo. Mechanistically, CAMK2G directly senses ROS, both basal and cisplatin-induced, to control the phosphorylation of ITPKB at serine 174, which directly regulates ITPKB activity to modulate cisplatin-induced ROS stress. Thereby, CAMK2G facilitates the adaptive redox homeostasis upon cisplatin treatment and drives cisplatin resistance. Clinically, upregulation of CAMK2G activity and ITPKB pS174 correlates with cisplatin resistance in human ovarian cancers. This study reveals a key kinase network consisting of CAMK2G and ITPKB for ROS sense and scavenging in ovarian cancer cells to maintain redox homeostasis, offering a potential strategy for cisplatin resistance treatment.

Circular RNA hsa_circ_0043280 inhibits cervical cancer tumor growth and metastasis via miR-203a-3p/PAQR3 axis

AbstractCircular RNAs (circRNAs) are known to act as key regulators in a variety of malignancies. However, the role of circRNAs in cervical cancer (CCa) remains largely unknown. Herein, we demonstrated that a circRNA derived from the TADA2A gene (hsa_circ_0043280) was significantly downregulated in CCa and that this reduction in expression was correlated with a poor prognosis. Furthermore, our results demonstrated that hsa_circ_0043280 functions as a tumor suppressor to inhibit tumor growth and metastasis in CCa. Mechanistically, hsa_circ_0043280 competitively sponges miR-203a-3p and prevents miR-203a-3p from reducing the levels of PAQR3. Collectively, our results demonstrate that hsa_circ_0043280 plays a pivotal role in the development and metastasis of CCa, thus suggesting that hsa_circ_0043280 has significant potential as a prognostic biomarker and a therapeutic target for CCa.

Family with sequence similarity 83 member A promotes tumor cell proliferation and metastasis and predicts poor prognosis in cervical cancer

Family with sequence similarity 83 member A (FAM83A) is a member of the FAM83 family and is proven to have oncogenic properties in several cancers. However, the mechanisms of FAM83A in human cervical cancer (CC) progression are unknown. Here, we found that FAM83A is highly expressed in CC tissues and cell lines through western blot and qRT-PCR. We utilized GEO datasets to assess FAM83A expression in CC in comparison to the normal cervical tissue (NCT) (GSE6791), and similarly, in lymph node positive CC compared to the lymph node negative CC (GSE26511). Immunohistochemistry (IHC) was used to quantify FAM83A expression in 20 NCT and 105 CC patient samples. FAM83A expression is upregulated in early-stage CC and correlates with aggressive clinicopathologic features. Moreover, both our hospital's and TCGA datasets revealed that patients of early-stage CC with higher FAM83A expression had a poorer prognosis. Subsequently, CCK-8 and transwell assays verified that FAM83A promotes proliferation, migration, and invasion of CC cells. Additionally, Gene Set Enrichment Analysis (GSEA) revealed that FAM83A is not only involved in cell development, differentiation, and proliferation but is also correlated with cell junction assembly and cell matrix adhesion. It might also be affiliated with the regulation of tumor necrosis factor-mediated signaling pathway and the regulation of the ErbB signaling pathway in CC. These results indicate that FAM83A promotes tumor cell proliferation, migration, and metastasis. Our study provides novel evidence FAM83A may act as a promising therapeutic target for CC.

FASN promotes lymph node metastasis in cervical cancer via cholesterol reprogramming and lymphangiogenesis

AbstractCervical cancer (CC) patients with lymph node metastasis (LNM) have a poor prognosis. Clarification of the detailed mechanisms underlying LNM may provide potential clinical therapeutic targets for CC patients with LNM. However, the molecular mechanism of LNM in CC is unclear. In the present study, we demonstrated that fatty acid synthase (FASN), one of the key enzymes in lipid metabolism, had upregulated expression in the CC samples and was correlated with LNM. Moreover, multivariate Cox proportional hazards analysis identified FASN as an independent prognostic factor of CC patients. Furthermore, gain-of-function and loss-of-function approaches showed that FASN promoted CC cell migration, invasion, and lymphangiogenesis. Mechanistically, on the one hand, FASN could regulate cholesterol reprogramming and then activate the lipid raft-related c-Src/AKT/FAK signaling pathway, leading to enhanced cell migration and invasion. On the other hand, FASN induced lymphangiogenesis by secreting PDGF-AA/IGFBP3. More importantly, knockdown of FASN with FASN shRNA or the inhibitors C75 and Cerulenin dramatically diminished LNM in vivo, suggesting that FASN plays an essential role in LNM of CC and the clinical application potential of FASN inhibitors. Taken together, our findings uncover a novel molecular mechanism in LNM of CC and identify FASN as a novel prognostic factor and potential therapeutic target for LNM in CC.

Downregulation of LNMAS orchestrates partial EMT and immune escape from macrophage phagocytosis to promote lymph node metastasis of cervical cancer

AbstractEpithelial-mesenchymal transition (EMT) is an essential step to drive the metastatic cascade to lymph nodes (LNs) in cervical cancer cells. However, few of them metastasize successfully partially due to increased susceptibility to immunosurveillance conferred by EMT. The precise mechanisms of cancer cells orchestrate EMT and immune evasion remain largely unexplored. In this study, we identified a lncRNA termed lymph node metastasis associated suppressor (LNMAS), which was downregulated in LN-positive cervical cancer patients and correlated with LN metastasis and prognosis. Functionally, LNMAS suppressed cervical cancer cells metastasis in vitro and in vivo. Mechanistically, LNMAS exerts its metastasis suppressive activity by competitively interacting with HMGB1 and abrogating the chromatin accessibility of TWIST1 and STC1, inhibiting TWIST1-mediated partial EMT and STC1-dependent immune escape from macrophage phagocytosis. We further demonstrated that the CpG sites in the promoter region of LNMAS was hypermethylated and contributed to the downregulation of LNMAS. Taken together, our results reveal the essential role of LNMAS in the LN metastasis of cervical cancer and provide mechanistic insights into the regulation of LNMAS in EMT and immune evasion.