Abstract
Background
Noise‐induced hearing loss (NIHL) is a key occupational hazard, and its specific pathogenic mechanism is not fully elucidated. Here, we performed this study to explore the potential role of single nucleotide polymorphisms (SNPs) located in the
PI3K/AKT
pathway in human susceptibility to NIHL.
Methods
A case‐control study including 688 NIHL patients and 667 normal subjects was conducted. Genotype analysis was tested by multiplex polymerase chain reaction (PCR) with next generation sequencing. Luciferase assays were conducted to explore the effect of
SP1
on
PIK3R3
promoter activity. siRNA and cell transfection were used to determine the regulatory effect of
SP1/PIK3R3
on HEI‐OC1 cells. qRT‐PCR and Western blotting were used to determine the expression of genes and proteins related to
PI3K/AKT
, autophagy, and apoptosis. Cell counting kit 8 (CCK‐8) assay was used to detect cell viability.
Results
Subjects with
PIK3R3
rs7536272 GG genotype were more sensitive to NIHL than those with the AA/AG genotypes and had a lower expression level of
PIK3R3
. Luciferase assay indicated that rs7536272 regulated
PIK3R3
expression by binding to
SP1
. Knockdown of
SP1
by siRNA and transfection into HEI‐OC1 cells inhibited the
PI3K/AKT
pathway, indicated by the decreased phosphorylation levels of
PI3K
and
AKT
. Concurrently,
SP1
deficiency promoted autophagy, as evidenced by an elevated
LC3-II/LC3-I
ratio and induced apoptosis, characterized by the reduction of
Bcl2
and the increase of
Bax
and
caspase-3
. Overexpression of
PIK3R3
partially restored the decreased activity of
PI3K/AKT
pathway and attenuated the enhanced autophagy and apoptosis caused by
SP1
deficiency. CCK‐8 assay revealed that
SP1
knockdown led to a time‐dependent decrease in cell viability, which was significantly rescued by the overexpression of
PIK3R3
.
Conclusion
All findings demonstrate that rs7536272 influences NIHL susceptibility by regulating
PIK3R3
expression in an allele‐specific manner by binding to
SP1
.
SP1
inhibits autophagy and apoptosis by activating
PIK3R3
‐mediated
PI3K/AKT
pathway.