HERES, a lncRNA that regulates canonical and noncanonical Wnt signaling pathways via interaction with EZH2

Area of Science:

• Molecular Biology
• Cancer Research
• Epigenetics

Background:

• Wnt signaling pathways are crucial in development and their dysregulation is linked to cancer.
• Canonical and noncanonical Wnt pathways are independently regulated, with no known common activator.
• Esophageal squamous cell carcinoma (ESCC) progression involves complex molecular mechanisms.

Purpose of the Study:

• To identify novel regulatory molecules in ESCC.
• To investigate the role of long noncoding RNAs (lncRNAs) in Wnt signaling.
• To explore HERES as a potential therapeutic target in ESCC.

Main Methods:

• RNA sequencing (RNA-seq) on Korean ESCC patient cohorts.
• Validation of lncRNA dysregulation in a larger ESCC cohort.
• Functional assays including cell proliferation, migration, invasion, colony formation, and xenograft models.
• Investigation of HERES interaction with EZH2 and target genes (CACNA2D3, SFRP2, CXXC4).

Main Results:

• Identified HERES, a lncRNA, that epigenetically regulates both canonical and noncanonical Wnt signaling in ESCC.
• HERES dysregulation was associated with clinical outcomes and defined prognostic subclasses in ESCC.
• HERES reduction inhibited ESCC cell proliferation, migration, invasion, colony formation, and tumor growth.
• HERES acts as a transacting factor, interacting with EZH2 to regulate Wnt pathway genes.

Conclusions:

• HERES is a key regulator of Wnt signaling in ESCC.
• HERES demonstrates significant potential as a therapeutic target for ESCC.
• The findings suggest HERES may also be relevant for other cancers involving Wnt pathway defects.