Title:SETD1A-mediated Methylation of H3K4me3 Inhibits Ferroptosis in
Non-small Cell Lung Cancer by Regulating the WTAPP1/WTAP Axis
Volume: 31
Issue: 21
Author(s): Dao Wang, Yukun Zu, Wei Sun and Xiaowu Fan*
Affiliation:
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science
and Technology, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei Province, 430030, China
Keywords:
Non-small cell lung cancer, SETD1A, H3K4me3, epigenetics, WTAPP1, WTAP, ferroptosis.
Abstract:
Introduction: SETD1A is upregulated in non-small cell lung cancer (NSCLC)
tissues. This study investigated the molecular mechanism of the SETD1A/WTAPP1/WTAP
axis in NSCLC.
Methods: Ferroptosis is a unique cell death mode driven by iron-reliant phospholipid peroxidation,
which is regulated by multiple cellular metabolic pathways, including REDOX
homeostasis, iron metabolism, mitochondrial activity and metabolism of amino
acids, lipids and sugars. Thus, the levels of ferroptosis markers (MDA, SOD, GSH) were
measured in vitro, and NSCLC cell behaviors were assessed. SETD1A-mediated
H3K4me3 methylation was analyzed. SETD1A-exerted effects on ferroptosis and tumor
growth in vivo were verified in nude mouse models.
Results: SETD1A was highly expressed in NSCLC cells. Silencing SETD1A suppressed
NSCLC cell proliferation and migration, inhibited MDA, and enhanced GPX4, SOD, and
GSH levels. SETD1A elevated WTAP expression through WTAPP1 upregulation by mediating
H3K4me3 methylation in the WTAPP1 promoter region. WTAPP1 overexpression
partly averted the promotional effect of silencing SETD1A on NSCLC cell ferroptosis.
WTAP interference abrogated the inhibitory effects of WTAPP1 on NSCLC cell ferroptosis.
Silencing SETD1A facilitated ferroptosis and accelerated tumor growth in nude
mice through the WTAPP1/WTAP axis.
Conclusion: SETD1A amplified WTAP expression through WTAPP1 upregulation by
mediating H3K4me3 modification in the WTAPP1 promoter region, thus promoting NSCLC
cell proliferation and migration and inhibiting ferroptosis.