Unravelling the Role of Iroquois Homeobox 4 and its Interplay with Androgen Receptor in Prostate Cancer.

Genome-wide association studies have linked Iroquois-Homeobox 4 (IRX4) as a robust expression quantitative-trait locus associated with prostate cancer (PCa) risk. However, the intricate mechanism and regulatory factors governing IRX4 expression in PCa remain poorly understood. Here, we unveil enrichment of androgen-responsive gene signatures in metastatic prostate tumors exhibiting heightened IRX4 expression. Furthermore, we uncover a novel interaction between IRX4 and the androgen receptor (AR) co-factor, FOXA1, suggesting that IRX4 modulates PCa cell behavior through AR cistrome alteration. Remarkably, we identified a distinctive short insertion-deletion polymorphism (INDEL), upstream of the IRX4 gene that differentially regulates IRX4 expression through the disruption of AR binding. This INDEL emerges as the most significant PCa risk-associated variant within the 5p15 locus, in a genetic analysis involving 82,591 PCa cases and 61,213 controls and was associated with PCa survival in patients undergoing androgen-deprivation therapy. These studies suggest the potential of this INDEL as a prognostic biomarker for androgen therapy in PCa and IRX4 as a potential therapeutic target in combination with current clinical management.

Severe COVID-19 May Impact Hepatic Fibrosis /Hepatic Stellate Cells Activation as Indicated by a Pathway and Population Genetic Study.

Coronavirus disease 19 (COVID-19) has affected over 112 million people and killed more than 2.5 million worldwide. When the pandemic was declared, Spain and Italy accounted for 29% of the total COVID-19 related deaths in Europe, while most infected patients did not present severe illness. We hypothesised that shared genomic characteristics, distinct from the rest of Europe, could be a contributor factor to a poor prognosis in these two populations. To identify pathways related to COVID-19 severity, we shortlisted 437 candidate genes associated with host viral intake and immune evasion from SARS-like viruses. From these, 21 were associated specifically with clinically aggressive COVID-19. To determine the potential mechanism of viral infections, we performed signalling pathway analysis with either the full list (n = 437) or the subset group (n = 21) of genes. Four pathways were significantly associated with the full gene list (Caveolar-mediated Endocytosis and the MSP-RON Signalling) or with the aggressive gene list (Hepatic Fibrosis/Hepatic Stellate Cell (HSC) Activation and the Communication between Innate and Adaptive Immune Cells). Single nucleotide polymorphisms (SNPs) from the ±1 Mb window of all genes related to these four pathways were retrieved from the dbSNP database. We then performed Principal Component analysis for these SNPs in individuals from the 1000 Genomes of European ancestry. Only the Hepatic Fibrosis/HSC Activation pathway showed population-specific segregation. The Spanish and Italian populations clustered together and away from the rest of the European ancestries, with the first segregating further from the rest. Additional in silico analysis identified potential genetic markers and clinically actionable therapeutic targets in this pathway, that may explain the severe disease.

Long Non-Coding RNAs at the Chromosomal Risk Loci Identified by Prostate and Breast Cancer GWAS.

Long non-coding RNAs (lncRNAs) are emerging as key players in a variety of cellular processes. Deregulation of the lncRNAs has been implicated in prostate and breast cancers. Recently, germline genetic variations associated with cancer risk have been correlated with lncRNA expression and/or function. In addition, single nucleotide polymorphisms (SNPs) at well-characterized cancer-associated lncRNAs have been analyzed for their association with cancer risk. These SNPs may occur within the lncRNA transcripts or spanning regions that may alter the structure, function, and expression of these lncRNA molecules and contribute to cancer progression and may have potential as therapeutic targets for cancer treatment. Additionally, some of these lncRNA have a tissue-specific expression profile, suggesting them as biomarkers for specific cancers. In this review, we highlight some of the cancer risk-associated SNPs that modulated lncRNAs with a potential role in prostate and breast cancers and speculate on how these lncRNAs may contribute to cancer development.

Identification and Characterization of Alternatively Spliced Transcript Isoforms of IRX4 in Prostate Cancer.

Alternative splicing (AS) is tightly regulated to maintain genomic stability in humans. However, tumor growth, metastasis and therapy resistance benefit from aberrant RNA splicing. Iroquois-class homeodomain protein 4 (IRX4) is a TALE homeobox transcription factor which has been implicated in prostate cancer (PCa) as a tumor suppressor through genome-wide association studies (GWAS) and functional follow-up studies. In the current study, we characterized 12 IRX4 transcripts in PCa cell lines, including seven novel transcripts by RT-PCR and sequencing. They demonstrate unique expression profiles between androgen-responsive and nonresponsive cell lines. These transcripts were significantly overexpressed in PCa cell lines and the cancer genome atlas program (TCGA) PCa clinical specimens, suggesting their probable involvement in PCa progression. Moreover, a PCa risk-associated SNP rs12653946 genotype GG was corelated with lower IRX4 transcript levels. Using mass spectrometry analysis, we identified two IRX4 protein isoforms (54.4 kDa, 57 kDa) comprising all the functional domains and two novel isoforms (40 kDa, 8.7 kDa) lacking functional domains. These IRX4 isoforms might induce distinct functional programming that could contribute to PCa hallmarks, thus providing novel insights into diagnostic, prognostic and therapeutic significance in PCa management.