LncRNA LMCD1-AS1 Interacts with PHF8 to Promote Hepatocellular Carcinoma Resistance to Multikinase Inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Multikinase inhibitors (MKIs) like sorafenib and lenvatinib are first-line treatments for hepatocellular carcinoma (HCC).
• Resistance to MKIs significantly limits treatment efficacy in HCC.
• The role of long non-coding RNAs (lncRNAs) in MKI resistance remains largely unexplored.

Purpose of the Study:

• To identify lncRNAs involved in MKI resistance in HCC.
• To elucidate the molecular mechanisms by which lncRNAs mediate resistance to sorafenib and lenvatinib.
• To evaluate LMCD1-AS1 as a potential therapeutic target and prognostic biomarker in HCC.

Main Methods:

• Integrated analysis of resistant HCC models.
• Overexpression and knockdown studies of lncRNA LMCD1-AS1.
• Assessment of apoptosis, drug sensitivity, and epigenetic modifications (H4K20me1).
• Investigation of interactions between LMCD1-AS1, PHF8, oncogenes, and metabolic enzymes (LDHA).
• In vivo xenograft studies in mice.

Main Results:

• lncRNA LMCD1-AS1 was identified as a key driver of MKI resistance in HCC.
• LMCD1-AS1 overexpression correlates with advanced HCC stage, poor survival, and resistance to sorafenib and lenvatinib.
• LMCD1-AS1 suppresses apoptosis and promotes resistance by interacting with PHF8, leading to epigenetic activation of oncogenes and upregulation of LDHA.
• This epigenetic-metabolic reprogramming results in lactate overproduction and altered NAD+/NADH ratio, creating a protumorigenic state.
• PHF8 inhibition reversed LMCD1-AS1-mediated resistance, and LMCD1-AS1 overexpression attenuated sorafenib efficacy in vivo.

Conclusions:

• The LMCD1-AS1/PHF8/H4K20me1 axis represents a novel epigenetic-metabolic mechanism driving MKI resistance in HCC.
• LMCD1-AS1 is a promising therapeutic target for overcoming MKI resistance.
• LMCD1-AS1 serves as a potential prognostic biomarker for HCC patients undergoing MKI therapy.