Hadhb Deficiency Inhibits Lung Tumorigenesis Via Activating ER Stress

Area of Science:

• Molecular Biology
• Oncology
• Mitochondrial Metabolism

Background:

• Lung cancer is a leading cause of cancer mortality globally.
• The molecular drivers of lung cancer are not fully understood.
• Mitochondrial dysfunction is increasingly implicated in cancer development.

Purpose of the Study:

• To identify novel oncogenes in lung cancer.
• To elucidate the role of HADHB in lung cancer pathogenesis.
• To investigate the therapeutic potential of targeting HADHB.

Main Methods:

• Utilized a HadhbPB/PB mouse model for K-RasG12D-driven lung cancer.
• Assessed cancer cell proliferation, apoptosis, and endoplasmic reticulum (ER) stress markers (ATF6(N), eIF2α phosphorylation, CHOP).
• Performed HADHB knockdown and CHOP knockdown experiments in vitro and in vivo.

Main Results:

• Hadhb deficiency suppressed K-RasG12D-driven lung tumor progression in mice.
• Hadhb loss induced proteotoxic ER stress and upregulated the pro-apoptotic factor CHOP.
• CHOP knockdown partially restored tumor growth, identifying it as a key downstream mediator.
• HADHBH protein was upregulated in human lung tumors, and low HADHB mRNA correlated with better prognosis.

Conclusions:

• HADHBH acts as a novel oncogene in lung cancer.
• A HADHB-CHOP regulatory axis is critical for lung cancer progression.
• Targeting mitochondrial metabolism and ER stress presents a potential therapeutic strategy for lung cancer.