Pallavi Agarwal

Introduction: Maternal Embryonic Leucine Zipper Kinase (MELK) is a serine/threonine protein kinase involved in regulating key cellular processes, including cell cycle progression, apoptosis, embryonic development, spliceosome assembly, and gene expression. Notably, MELK is overexpressed in Triple-Negative Breast Cancer (TNBC), an aggressive malignancy associated with poor prognosis, high drug resistance, and limited treatment options. Given its critical role in TNBC pathogenesis, MELK has emerged as a potential biomarker and therapeutic target. This review explores the molecular functions of MELK, its involvement in oncogenic signaling pathways, and the development of MELK-targeting small-molecule inhibitors. Methods: A comprehensive literature review was conducted to evaluate current knowledge on MELK, including its molecular functions, interactions within signaling pathways, role in TNBC progression, and potential as a therapeutic target. Relevant databases, including PubMed, Web of Science, Embase, and Scopus, were searched for studies related to MELK expression, signaling mechanisms, and experimental therapeutic approaches. Results: MELK plays a central role in oncogenic signaling pathways that drive TNBC proliferation and survival. Preclinical studies have demonstrated that MELK inhibition can suppress TNBC cell growth and enhance chemotherapy efficacy. Several small-molecule inhibitors targeting MELK have shown promising anti-tumor activity in preclinical models. However, challenges remain in translating these findings into clinical applications due to drug specificity limitations and resistance mechanisms. Conclusion: MELK is a promising biomarker and therapeutic target in TNBC. However, further research is required to refine MELK inhibitors, enhance clinical efficacy, and overcome drug resistance mechanisms. Targeting MELK could offer a novel therapeutic strategy to improve TNBC treatment outcomes.

Copy number gene amplification and associated overexpression of driver oncogenes are genetic events that contribute to cancer progression and drug resistance. MDS1 and EVI1 Complex locus (MECOM) gene is copy number amplified and overexpressed in aggressive epithelial ovarian cancers. The biological function and precise molecular mechanism of MECOM in the progression and drug resistance of ovarian cancer remain unclear. Here, we unravel MECOM as a regulator of KRAS and its downstream MAP Kinase signalling pathway, and also identify epigenetic inhibitor JIB-04 as a pharmacological agent targeting MECOM/KRAS axis. RNAi-mediated attenuation of MECOM in ovarian cancer cells harboring MECOM amplification reduced their proliferation, impaired colony formation, and impeded cellular migration. ChIP-qPCR analysis confirmed binding of MECOM to the KRAS promoter, suggesting direct regulation of the KRAS gene at the transcriptional level. Further, MECOM promoted cellular proliferation by regulating KRAS-mediated ERK/ZEB1 signalling cascade. The anti-tumorigenic effects due to MECOM loss were phenocopied by the treatment of ovarian cancer cells harboring MECOM amplification with JIB-04 epigenetic inhibitor targeting Jumonji domain histone demethylase enzymes. By ChIP-qPCR, we show that JIB-04 induced transcriptional changes of MECOM by altering H3K27me3 demethylation at its promoter region. We further report that ovarian cancer cells expressing high-MECOM levels exhibit cisplatin resistance, which could be effectively reversed upon pre-treatment with JIB-04. The therapeutic efficacy of JIB-04 was further demonstrated in mice bearing ovarian cancer cell xenografts, where JIB-04 slowed down the tumor growth in corroboration with diminishing MECOM expression. RNA-sequencing analysis identified potential cisplatin resistance gene, SUB1, being regulated by JIB-04-mediated modulation of MECOM expression. Altogether, these data suggest that epigenetic silencing of MECOM by JIB-04 mediated H3K27me3 modulation is an important mechanism in ovarian cancer and provide a new therapeutic target for the treatment of ovarian cancers harboring MECOM amplification.

Editorial: Genetic regulation of mitosis and ploidy in cancer

Cell division cycle 20 (CDC20), a critical partner of anaphase promoting complex (APC/C), is indispensably required for metaphase-to-anaphase transition. CDC20 overexpression in TNBC breast cancer patients has been found to be correlated with poor prognosis, hence, we aimed to target CDC20 for TNBC therapeutics. In silico molecular docking of large-scale chemical libraries (phytochemicals/synthetic drugs) against CDC20 protein structure identified five synthetic drugs and four phytochemicals as potential hits interacting with CDC20 active site. The molecular selection was done based on docking scores, binding interactions, binding energies and MM/GBSA scores. Further, we analysed ADME profiles for all the hits and identified lidocaine, an aminoamide anaesthetic group of synthetic drug, with high drug-likeness properties. We explored the anti-tumorigenic effects of lidocaine on MDA-MB-231 TNBC breast cancer cells, which resulted in increased growth inhibition in dose-dependent manner. The molecular mechanism behind the cell viability defect mediated by lidocaine was found to be induction of G2/M cell cycle arrest and cellular apoptosis. Notably, lidocaine treatment of TNBC cells also resulted in downregulation of CDC20 gene expression. Thus, this study identifies lidocaine as a potential anti-neoplastic agent for TNBC cells emphasizing CDC20 as a suitable therapeutic target for breast cancer.

BACKGROUND: The breast cancer subtype deficient in estrogen receptor and human epidermal growth factor receptor-2 (ER-/HER2-) displays enhanced aggressiveness, metastasis and disease relapse due to chemoresistance. ER-/HER2- patients lack molecularly targeted treatment hence, new therapeutic and prognostic biomarkers are required for better patient management. OBJECTIVES: To investigate the prognostic role of protein tyrosine phosphatase genes in Breast Cancer and their relevance as predictive markers for chemoresistance. METHODS: We examined the expression of 114 protein tyrosine phosphatase (PTP) genes in 1700 breast cancer patient’s tumor samples with respect to ER-/HER2- subtype. Correlation of relevant candidates with chemoresistance was analyzed in breast cancer cells resistant to taxane/anthracycline based drugs. The prognostic value of key candidates was assessed using Kaplan Meier plots and Nottingham prognostic index and expression pattern was confirmed using qRT-PCR. The epigenetic regulation was analyzed using ChIP-Seq datasets. By plotting ROC plots, clinical outcome after treatment with taxane and anthracycline was established. RESULTS: Overexpression of CDC25A and CDC25C and under-expression of DUSP16 was observed in tumor samples of ER-/HER2- patients and breast cancer cells. Similar expression patterns of these candidate genes were observed in MCF7 cells resistant to paclitaxel and adriamycin and also correlated with poor prognosis of breast cancer patients. Increased CDC25A and CDC25C in ER-/HER2- cells was found to be regulated epigenetically by histone H3K4 methylation. Overall, the present study establishes increased expression of protein tyrosine phosphatase CDC25C as a poor prognostic marker for breast cancer. CONCLUSION: Our study highlights the role of CDC25C in chemoresistance to taxane and anthracycline based therapy and proposes CDC25C as a potential predictive marker for these cancer therapies.

Background: High grade serous ovarian cancer (HGSOC) accounts for nearly 60% of total cases of epithelial ovarian cancer. It is the most aggressive subtype, which shows poor prognosis and low patient survival. For better management of HGSOC patients, new prognostic biomarkers are required to facilitate improved treatment strategies and ensure suitable healthcare decisions. Methods: We performed genome wide expression analysis of HGSOC patient samples to identify differentially expressed genes (DEGs) using R based Limma package, Clust and other statistical tools. The identified DEGs were subjected to weighted gene co-expression network analysis (WGCNA) to identify co-expression patterns of relevant genes. Module trait and gene ontology analyses were performed to establish important gene co-expression networks and their biological functions. Overlapping the most relevant DEG cluster 4 with prominent WGCNA cyan module identified strongest correlation of UBE2Q1 with ovarian cancer and its prognostic significance on survival probability of ovarian cancer patients was investigated. The predictive value of UBE2Q1 as a potential biomarker was analysed by correlating its expression with 12-months relapse free survival of patients in response to platin/taxane, the standard first-line chemotherapy for ovarian cancer, and analysing area under the ROC curve. Results: An integrated gene expression analysis and WGCNA, identified UBE2Q1 as a potential prognostic marker associated with poor relapse-free survival and response outcome to platin/taxane treatment of patients with high grade serous ovarian cancer. Conclusions: Our study identifies a potential UBE2Q1 – B4GALT3 functional axis in ovarian cancer, where only the E2 conjugating enzyme showed a poor prognostic impact on the disease.