HIF-1α is a master regulator of oxygen homeostasis involved in different stages of cancer development. Thus, HIF-1α inhibition represents an interesting target for anti-cancer therapy. It was recently shown that HIF-1α interaction with NQO1 inhibits its proteasomal degradation, thus suggesting that targeting the stability of NQO1 could led to destabilization of HIF-1α as a therapeutic approach. Since the molecular interactions of NQO1 with HIF-1α are beginning to be unraveled, we review here our current knowledge on the intracellular functions and stability of NQO1, its pharmacological modulation by small ligands, and the molecular determinants of its roles as a chaperone of many different proteins including cancer-associated factors such as p53 and p73α. This knowledge is then discussed in the context of potentially targeting the intracellular stability of HIF-1α by acting on its chaperone, NQO1. This could result in novel anti-cancer therapies.

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Purpose Around 70% of infertile men are diagnosed with idiopathic (abnormal semen parameters) or unexplained (normozoospermia) infertility, with the common feature of lacking etiologic. Follicle stimulating hormone (FSH) is essential for initiation and maintenance of spermatogenesis. Certain single nucleotide polymorphisms (SNP) (i.e. FSHB c.-211G>T, FSHR c.2039A>G) are associated with FSH, testicular volume and spermatogenesis. It is unknown to which extent other variants are associated with FSH levels and therewith resemble causative factors for infertility. Methods We retrospectively (2010-2018) selected 1900 men with idiopathic/unexplained infertility. In the discovery study (n=760) a Genome wide association study (GWAS) was performed (Infinium PsychArrays®) with association to FSH values (Illumina®GenomeStudiov2.0). Minor allele frequencies (MAFs) were analyzed for the discovery – and an independent normozoospermic cohort. In the validation study (n=1140) TaqMan SNP-PCR was conducted for rs10031005 and rs10835638 with association to andrological parameters. Results Imputation revealed nine SNPs in high linkage disequilibrium, with genome-wide significance (p <4.28e-07) at the FSHB locus 11p.14.1 being associated with FSH. The nine SNPs accounted for up to 4.65% variance in FSH level. In the oligozoospermic subgroup this was increased up to 6.95% and the MAF was enhanced compared to an independent cohort of normozoospermic men. By validation significant association for rs110031005/rs10835638 with FSH (p=4.71e-06/5.55e-07) and FSH/LH ratio (p=2.08e-12/6.4e-12) was evident. Conclusions This GWAS delineates the polymorphic FSHB genomic region as main determinant for FSH levels in men with unexplained or idiopathic infertility. Given the essential role of FSH, molecular detection of one of the identified SNPs, that cause lowered FSH and therewith decreased spermatogenesis, could resolve the idiopathic/unexplained origin by this etiologic factor.

We conducted a genome-wide association study in a large population of infertile men due to unexplained spermatogenic failure (SPGF). More than seven million genetic variants were analysed in 1,274 SPGF cases and 1,951 unaffected controls from two independent European cohorts. Two genomic regions were associated with the most severe histological pattern of SPGF, defined by Sertoli cell-only (SCO) phenotype, namely the MHC class II gene HLA-DRB1 (rs1136759, P = 1.32E-08, OR = 1.80) and an upstream locus of VRK1 (rs115054029, P = 4.24E-08, OR = 3.14), which encodes a protein kinase involved in the regulation of spermatogenesis. The SCO-associated rs1136759 allele (G) determines a serine in the position 13 of the HLA-DRβ1 molecule located in the antigen-binding pocket. Overall, our data support the notion of unexplained SPGF as a complex trait influenced by common variation in the genome, with the SCO phenotype likely representing an immune-mediated condition.

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