HSPB6 based on integrative multi-omics analysis can suppress colorectal cancer progression by downregulating HSPA6 expression through the JNK-JUND axis.

Aims: Colorectal cancer (CRC) remains one of the most common malignancies worldwide characterized by poor prognosis, and its mechanism is unclear. Small heat shock protein 6 (HSPB6) plays an important role in cardiovascular diseases. However, the role of HSPB6 in CRC remain poorly understood.

Materials and methods: We performed whole-genome methylation, RNA sequencing and proteomics analysis, combined with external database, to identify and validate the role of HSPB6 in CRC. We detected HSPB6 in CRC through in vitro and in vivo experiments. The downstream regulatory mechanism of HSPB6 was explored using RNA sequencing and immunoprecipitation mass spectrometry. The drug sensitivity assay conducted to evaluate the effect of HSPB6 expression on chemosensitivity.

Key findings: HSPB6 was hypermethylated and downregulated in CRC tissues, and its expression level was correlated with poor patient prognosis. Both the methylation and expression of HSPB6 showed high diagnostic value. Overexpression of HSPB6 inhibited proliferation, migration and invasion of CRC cells and suppress tumor growth in mice. HSPB6 directly interacted with Heat shock protein family A member 6 (HSPA6), leading to inhibition of the JNK-JUND axis. Additionally, HSPB6 overexpression increased sensitivity to oxaliplatin.

Significance: HSPB6 may serve as a valuable diagnostic and prognostic biomarker, and as a putative tumor suppressor in CRC by downregulating HSPA6 and inhibiting the JNK-JUND signaling axis. Our findings suggest a novel therapeutic strategy for CRC patients exhibiting high HSPB6 expression, particularly in the context of oxaliplatin treatment.