HN1 is a novel dedifferentiation factor involved in regulating the cell cycle and microtubules in SH-SY5Y neuroblastoma cells.

Hematological and neurological expressed 1 (HN1), encoding a small protein, has been recently explored in different cancers owing to its higher expression in tumor samples as compared to adjacent normal. It was discovered and subsequently named because of its higher expression in hematological and neurological tissues in developing mice. Following discovery, it was considered a neuronal regeneration or dedifferentiation-related gene. However, since then, it has not been characterized in neuroblastoma or differentiated neurons. SH-SY5Y cell line presents a unique model of neuroblastoma often utilized in neurobiology research. In this study, first, we employed bioinformatics analysis along with in vitro evaluation using normal and retinoic acid (RA)-differentiated SH-SY5Y cells to determine the responses of HN1 and its function. The analysis revealed that HN1 expression is higher in neuroblastoma and lower in differentiated neurons and Parkinson's disease as compared to appropriate controls. Since HN1 coexpression network in neuroblastoma is found to be enriched in cell-cycle-related pathways, we have shown that HN1 expression increases in S-phase and remains lower in the rest of the cell cycle phases. Moreover, HN1 expression is also correlated with the microtubule stability in SH-SY5Y cells, which was investigated with nocodazole and taxol treatments. HN1 overexpression increased the ratio of S-type cells (undifferentiated), indicating that it acts as a dedifferentiating factor in neuroblastoma cells. Moreover, cell cycle dynamics also changed upon HN1 overexpression with alternating effects on SH-SY5Y and RA-differentiated (N-type) cells. Therefore, HN1 is a potential cell cycle regulatory element in the development of neuroblastoma or dedifferentiation of neurons, which requires further studies to decipher its mechanistic role.

Clinical and Preclinical Targeting of Oncogenic Pathways in PDAC: Targeted Therapeutic Approaches for the Deadliest Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide. It is commonly diagnosed in advanced stages and therapeutic interventions are typically constrained to systemic chemotherapy, which yields only modest clinical outcomes. In this review, we examine recent developments in targeted therapy tailored to address distinct molecular pathway alteration required for PDAC. Our review delineates the principal signaling pathways and molecular mechanisms implicated in the initiation and progression of PDAC. Subsequently, we provide an overview of prevailing guidelines, ongoing investigations, and prospective research trajectories related to targeted therapeutic interventions, drawing insights from randomized clinical trials and other pertinent studies. This review focus on a comprehensive examination of preclinical and clinical data substantiating the efficacy of these therapeutic modalities, emphasizing the potential of combinatorial regimens and novel therapies to enhance the quality of life for individuals afflicted with PDAC. Lastly, the review delves into the contemporary application and ongoing research endeavors concerning targeted therapy for PDAC. This synthesis serves to bridge the molecular elucidation of PDAC with its clinical implications, the evolution of innovative therapeutic strategies, and the changing landscape of treatment approaches.

Mitotic kinase inhibitors as Therapeutic Interventions for Prostate Cancer: Evidence from In vitro Studies.

Prostate cancer is one of the devastating diseases characterized by genetic changes leading to uncontrolled growth and metastasis of the cells of the prostate gland and affects men worldwide. Conventional hormonal and chemotherapeutic agents are effective in mitigating the disease if diagnosed at an early stage. All dividing eukaryotic cells require mitotic progression for the maintenance of genomic integrity in progeny populations. The protein kinases, upon activation and de-activation in an ordered fashion, lead to spatial and temporal regulation of the cell division process. The entry into mitosis along with the progression into sub-phases of mitosis is ensured due to the activity of mitotic kinases. These kinases include Polo-Like-Kinase 1 (PLK1), Aurora kinases, and Cyclin-Dependent-Kinase 1 (CDK1), among others. The mitotic kinases, among others, are usually overexpressed in many cancers and can be targeted using small molecule inhibitors to reduce the effects of these regulators on mechanisms, such as regulation of genomic integrity and mitotic fidelity. In this review, we attempted to discuss the appropriate functions of mitotic kinases revealed through cell culture studies and the impact of their respective inhibitors derived in pre-clinical studies. The review is designed to elucidate the growing field of small molecule inhibitors and their functional screening or mode of action at the cellular and molecular level in the context of Prostate Cancer. Therefore, studies performed specifically on cells of Prostatic-origin are narrated in this review, culminating in a comprehensive view of the specific field of mitotic kinases that can be targeted for therapy of Prostate cancer.

The Regulation of Cyclins and Cyclin-Dependent Kinases in the Development of Gastric Cancer.

Gastric cancer predominantly occurs in adenocarcinoma form and is characterized by uncontrolled growth and metastases of gastric epithelial cells. The growth of gastric cells is regulated by the action of several major cell cycle regulators including Cyclins and Cyclin-dependent kinases (CDKs), which act sequentially to modulate the life cycle of a living cell. It has been reported that inadequate or over-activity of these molecules leads to disturbances in cell cycle dynamics, which consequently results in gastric cancer development. Manny studies have reported the key roles of Cyclins and CDKs in the development and progression of the disease in either in vitro cell culture studies or in vivo models. We aimed to compile the evidence of molecules acting as regulators of both Cyclins and CDKs, i.e., upstream regulators either activating or inhibiting Cyclins and CDKs. The review entails an introduction to gastric cancer, along with an overview of the involvement of cell cycle regulation and focused on the regulation of various Cyclins and CDKs in gastric cancer. It can act as an extensive resource for developing new hypotheses for future studies.

HN1 Is Enriched in the S-Phase, Phosphorylated in Mitosis, and Contributes to Cyclin B1 Degradation in Prostate Cancer Cells.

HN1 has previously been shown as overexpressed in various cancers. In Prostate cancer, it regulates AR signaling and centrosome-related functions. Previously, in two different studies, HN1 expression has been observed as inversely correlated with Cyclin B1. However, HN1 interacting partners and the role of HN1 interactions in cell cycle pathways have not been completely elucidated. Therefore, we used Prostate cancer cell lines again and utilized both transient and stable inducible overexpression systems to delineate the role of HN1 in the cell cycle. HN1 characterization was performed using treatments of kinase inhibitors, western blotting, flow cytometry, immunofluorescence, cellular fractionation, and immunoprecipitation approaches. Our findings suggest that HN1 overexpression before mitosis (post-G2), using both transient and stable expression systems, leads to S-phase accumulation and causes early mitotic exit after post-G2 overexpression. Mechanistically, HN1 interacted with Cyclin B1 and increased its degradation via ubiquitination through stabilized Cdh1, which is a co-factor of the APC/C complex. Stably HN1-expressing cells exhibited a reduced Cdt1 loading onto chromatin, demonstrating an exit from a G1 to S phenotype. We found HN1 and Cdh1 interaction as a new regulator of the Cyclin B1/CDK1 axis in mitotic regulation which can be explored further to dissect the roles of HN1 in the cell cycle.

The Role of LSD1 and LSD2 in Cancers of the Gastrointestinal System: An Update.

Epigenetic mechanisms are known to play a key role in cancer progression. Specifically, histone methylation involves reversible post-translational modification of histones that govern chromatin structure remodelling, genomic imprinting, gene expression, DNA damage repair, and meiotic crossover recombination, among other chromatin-based activities. Demethylases are enzymes that catalyse the demethylation of their substrate using a flavin adenine dinucleotide-dependent amine oxidation process. Lysine-specific demethylase 1 (LSD1) and its homolog, lysine-specific demethylase 2 (LSD2), are overexpressed in a variety of human cancer types and, thus, regulate tumour progression. In this review, we focus on the literature from the last 5 years concerning the role of LSD1 and LSD2 in the main gastrointestinal cancers (i.e., gastric cancer, liver cancer, pancreatic cancer, and colorectal cancer).

HN1 interacts with γ-tubulin to regulate centrosomes in advanced prostate cancer cells.

Prostate cancer is one of the most common cancer for men worldwide with advanced forms showing supernumerary or clustered centrosomes. Hematological and neurological expressed 1 (HN1) also known as Jupiter Microtubule Associated Homolog 1 (JPT1) belongs to a small poorly understood family of genes that are evolutionarily conserved across vertebrate species. The co-expression network of HN1 from the TCGA PRAD dataset indicates the putative role of HN1 in centrosome-related processes in the context of prostate cancer. HN1 expression is low in normal RWPE-1 cells as compared to cancerous androgen-responsive LNCaP and androgen insensitive PC-3 cells. HN1 overexpression resulted in differential response for cell proliferation and cell cycle changes in RWPE-1, LNCaP, and PC-3 cells. Since HN1 overexpression increased the proliferation rate in PC-3 cells, these cells were used for functional characterization of HN1 in advanced prostate carcinogenesis. Furthermore, alterations in HN expression led to an increase in abnormal to normal nuclei ratio and increased chromosomal aberrations in PC-3 cells. We observed the co-localization of HN1 with γ-tubulin foci in prostate cancer cells, further validated by immunoprecipitation. HN1 was observed as physically associated with γ-tubulin and its depletion led to increased γ-tubulin foci and disruption in microtubule spindle assembly. Higher HN1 expression was correlated with prostate cancer as compared to normal tissues. The restoration of HN1 expression after silencing suggested that it has a role in centrosome clustering, implicating a potential role of HN1 in cell division as well as in prostate carcinogenesis warranting further studies.