Inhibin Alpha-Subunit (INHA) Expression in Adrenocortical Cancer Is Linked to Genetic and Epigenetic INHA Promoter Variation

Abstract

Adrenocortical carcinoma (ACC) is a rare, but highly malignant tumor of unknown origin. Inhibin α-subunit (Inha) knockout mice develop ACCs following gonadectomy. In man, INHA expression varies widely within ACC tissues and its circulating peptide inhibin pro-αC has been described as a novel tumor marker for ACC. We investigated whether genetic and epigenetic changes of the INHA gene in human ACC cause loss or variation of INHA expression. To this end, analyses of INHA sequence, promoter methylation and mRNA expression were performed in human adrenocortical tissues. Serum inhibin pro-αC levels were also measured in ACC patients. INHA genetic analysis in 37 unique ACCs revealed 10 novel, heterozygous rare variants. Of the 3 coding bases affected, one variant was synonymous and two were missense variants: S72F and S184F. The minor allele of rs11893842 at −124 bp was observed at a low frequency (24%) in ACC samples and was associated with decreased INHA mRNA levels: 4.7±1.9 arbitrary units for AA, compared to 26±11 for AG/GG genotypes (P = 0.034). The methylation of four proximal INHA promoter CpGs was aberrantly increased in five ACCs (47.7±3.9%), compared to normal adrenals (18.4±0.6%, P = 0.0052), whereas the other 14 ACCs studied showed diminished promoter methylation (9.8±1.1%, P = 0.020). CpG methylation was inversely correlated to INHA mRNA levels in ACCs (r = −0.701, p = 0.0036), but not associated with serum inhibin pro-αC levels. In conclusion, aberrant methylation and common genetic variation in the INHA promoter occur in human ACCs and are associated with decreased INHA expression.

Hypoxia-induced inhibin promotes tumor growth and vascular permeability in ovarian cancers

“…In prostate and adrenocortical cancers reports of both increased and decreased inhibinα levels have been reported 15 , 61 , 62 . In adrenocortical tumors with lower INHA levels, methylation of the INHA promoter was reported to occur at the CpG island within the proximal HRE site that we identified, suggesting potential roles for epigenetic regulation of INHA as well 62 . HIF transcription factors have reduced binding to methylated hypoxia response elements 63 .…”

Identification of Immune-Related Gene Signatures in Lung Adenocarcinoma and Lung Squamous Cell Carcinoma

“…The generation of IFN-γ is significantly enhanced by antigen-stimulated T cells in physiological concentrations of VIP, and it was reported that the enhancement of IFN-γ secretion was increased up to a maximum of 14-fold for the VIPR2-selective agonist ( 56 ). INHA encoded a member of TGF-beta superfamily of proteins to regulate multiple cellular processes, including cell proliferation, apoptosis, hormone secretion, and immune response ( 57 ). The construction of immune-related-gene-signature prognostic models in LUAD and LUSC would promote individualized treatment and provide potential novel targets for immunotherapy.…”

Hypoxia Regulated Inhibin Promotes Tumor Growth and Vascular Permeability By ACVRL1 and CD105 Dependent VE-Cadherin Internalization

“…In prostate and adrenocortical cancers reports of both increased and decreased inhibinα levels have been reported 15,69,70 . In adrenocortical tumors with lower INHA levels, methylation of the INHA promoter was reported to occur at the CpG island within the proximal HRE site that we identi ed, suggesting potential roles for epigenetic regulation of INHA as well 70 . HIF transcription factors have reduced binding to methylated hypoxia response elements 71 .…”