The Hippo signaling pathway has been established as a key regulator of organ size control, tumor suppression, and tissue regeneration in multiple organisms. Recently, emerging evidence has indicated that Hippo signaling might play an important role in regulating the immune system in both Drosophila and mammals. In particular, patients bearing a loss-of-function mutation of MST1 are reported to have an autosomal recessive primary immunodeficiency syndrome. MST1/2 kinases, the mammalian orthologs of Drosophila Hippo, may activate the non-canonical Hippo signaling pathway via MOB1A/B and/or NDR1/2 or cross-talk with other essential signaling pathways to regulate both innate and adaptive immunity. In this review, we present and discuss recent findings of cellular mechanisms/functions of Hippo signaling in the innate immunity in Drosophila and in mammals, T cell immunity, as well as the implications of Hippo signaling for tumor immunity.

/pdf/role-of-hippo-signaling-in-regulating-immunity-34ck9avylx.pdf

Role of Hippo signaling in regulating immunity

Despite recent efforts, prostate cancer (PCa) remains one of the most common cancers in men. Currently, there is no effective treatment for castration-resistant prostate cancer (CRPC). There is, therefore, an urgent need to identify new therapeutic targets. The Hippo pathway and its downstream effectors-the transcriptional co-activators, Yes-associated protein (YAP) and its paralog, transcriptional co-activator with PDZ-binding motif (TAZ)-are foremost regulators of stem cells and cancer biology. Defective Hippo pathway signaling and YAP/TAZ hyperactivation are common across various cancers. Here, we draw on insights learned from other types of cancers and review the latest advances linking the Hippo pathway and YAP/TAZ to PCa onset and progression. We examine the regulatory interaction between Hippo-YAP/TAZ and the androgen receptor (AR), as main regulators of PCa development, and how uncontrolled expression of YAP/TAZ drives castration resistance by inducing cellular stemness. Finally, we survey the potential therapeutic targeting of the Hippo pathway and YAP/TAZ to overcome PCa.

/pdf/the-hippo-pathway-in-prostate-cancer-1ven43wdfo.pdf

The Hippo Pathway in Prostate Cancer.

The classic understanding of molecular disease-mechanisms is largely based on protein-centric models. During the past decade however, genetic studies have identified numerous disease-loci in the human genome that do not encode proteins. Such non-coding DNA variants increasingly gain attention in diagnostics and personalized medicine. Of particular interest are long non-coding RNA (lncRNA) genes, which generate transcripts longer than 200 nucleotides that are not translated into proteins. While most of the estimated ~20,000 lncRNAs currently remain of unknown function, a growing number of genetic studies link lncRNA gene aberrations with the development of human diseases, including diabetes, AIDS, inflammatory bowel disease, or cancer. This suggests that the protein-centric view of human diseases does not capture the full complexity of molecular patho-mechanisms, with important consequences for molecular diagnostics and therapy. This review illustrates well-documented lncRNA gene aberrations causatively linked to human diseases and discusses potential lessons for molecular disease models, diagnostics, and therapy.

/pdf/disease-causing-mutations-and-rearrangements-in-long-non-3s7xkg1rtb.pdf

Disease-Causing Mutations and Rearrangements in Long Non-coding RNA Gene Loci.

Synthetic lethality is emerging as an important cancer therapeutic paradigm, while the comprehensive selective treatment opportunities for various tumors have not yet been explored. We develop the Synthetic Lethality Knowledge Graph (SLKG), presenting the tumor therapy landscape of synthetic lethality (SL) and synthetic dosage lethality (SDL). SLKG integrates the large-scale entity of different tumors, drugs and drug targets by exploring a comprehensive set of SL and SDL pairs. The overall therapy landscape is prioritized to identify the best repurposable drug candidates and drug combinations with literature supports, in vitro pharmacologic evidence or clinical trial records. Finally, cladribine, an FDA-approved multiple sclerosis treatment drug, is selected and identified as a repurposable drug for treating melanoma with CDKN2A mutation by in vitro validation, serving as a demonstrating SLKG utility example for novel tumor therapy discovery. Collectively, SLKG forms the computational basis to uncover cancer-specific susceptibilities and therapy strategies based on the principle of synthetic lethality.

/pdf/the-tumor-therapy-landscape-of-synthetic-lethality-4x8r3y9lqt.pdf

The tumor therapy landscape of synthetic lethality

Ovarian cancer is one of the most lethal gynecological malignancies worldwide because it tends to be detected late, when the disease has already spread, and prognosis is poor. In this review we aim to highlight the importance of long non-coding RNAs (lncRNAs) in diagnosis, prognosis and treatment choice, to make progress towards increasingly personalized medicine in this malignancy. We review the effects of lncRNAs associated with ovarian cancer in the context of cancer hallmarks. We also discuss the molecular mechanisms by which lncRNAs become involved in cellular physiology; the onset, development and progression of ovarian cancer; and lncRNAs' regulatory mechanisms at the transcriptional, post-transcriptional and post-translational stages of gene expression. Finally, we compile a series of online resources useful for the study of lncRNAs, especially in the context of ovarian cancer. Future work required in the field is also discussed along with some concluding remarks.

https://www.mdpi.com/2072-6694/12/4/1020/pdf

The Challenges and Opportunities of LncRNAs in Ovarian Cancer Research and Clinical Use

Identification of driver copy number alterations in diverse cancer types and application in drug repositioning

The Hippo signaling pathway is a highly conserved pathway controlling organ size, cell proliferation, apoptosis and other biological functions. Recent studies have shown that Hippo signaling pathway also plays important roles in cancer initiation and progression. However, a database offering multi-omics analyses and visualization of Hippo pathway genes in cancer, as well as comprehensive Hippo regulatory relationships is still lacking. To fill this gap, we constructed the Regulation of the Hippo Pathway in Cancer Genome (RHPCG) database. Currently, RHPCG focuses on analyzing the 21 core Hippo-protein-encoding genes in over 10 000 patients across 33 TCGA (The Cancer Genome Atlas) cancer types at the levels of genomic, epigenomic and transcriptomic landscape. Concurrently, RHPCG provides in its motif section 11 regulatory motif types associated with 21 core Hippo pathway genes containing 180 miRNAs, 6182 lncRNAs, 728 circRNAs and 335 protein coding genes. Thus, RHPCG is a powerful tool that could help researchers understand gene alterations and regulatory mechanisms in the Hippo signaling pathway in cancer.

RHPCG: a database of the Regulation of the Hippo Pathway in Cancer Genome.

Synthetic lethal (SL) interactions occur when alterations in two genes lead to cell death but alteration in only one of them is not lethal. SL interactions provide a new strategy for molecular-targeted cancer therapy. Currently, there are few drugs targeting SL interactions that entered into clinical trials. Therefore, it is necessary to investigate the link between SL interactions and drug sensitivity of cancer cells systematically for drug development purpose. We identified SL interactions by integrating the high-throughput data from The Cancer Genome Atlas, small hairpin RNA data and genetic interactions of yeast. By integrating SL interactions from other studies, we tested whether the SL pairs that consist of drug target genes and the genes with genomic alterations are related with drug sensitivity of cancer cells. We found that only 6.26%∼34.61% of SL interactions showed the expected significant drug sensitivity using the pooled cancer cell line data from different tissues, but the proportion increased significantly to approximately 90% using the cancer cell line data for each specific tissue. From an independent pharmacogenomics data of 41 breast cancer cell lines, we found three SL interactions (ABL1-IFI16, ABL1-SLC50A1 and ABL1-SYT11) showed significantly better prognosis for the patients with both genes being altered than the patients with only one gene being altered, which partially supports the SL effect between the gene pairs. Our study not only provides a new way for unraveling the complex mechanisms of drug sensitivity but also suggests numerous potentially important drug targets for cancer therapy.

Link synthetic lethality to drug sensitivity of cancer cells.

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Identification of driver copy number alterations in diverse cancer types and application in drug repositioning

RHPCG: a database of the Regulation of the Hippo Pathway in Cancer Genome.

Link synthetic lethality to drug sensitivity of cancer cells.