HOXA10-HOXA9-derived small protein (HDSP)

HOXA10-HOXA9-derived small protein (HDSP) is a microprotein (112 amino acids) encoded by a noncanonical open reading frame within the lncRNA resulting from a readthrough transcript between the HOXA10 and HOXA9 genes on chromosome 7. HDSP is highly expressed in gastric cancer and promotes malignant cell proliferation, migration, and metastasis. Mechanistically, HDSP interacts with and stabilizes the oncogenic transcription factor MECOM by blocking its ubiquitination and degradation via TRIM25, thereby enhancing MECOM and SPINK1 expression and activating downstream EGFR signaling. This establishes a positive feedback loop that further increases HOXA10-HOXA9 transcription. HDSP knockdown suppresses gastric tumor growth in vivo, while it has also been shown that synthetic HDSP peptides can act as cancer neoantigens, eliciting anti-tumor immune responses in preclinical models. These findings support HDSP as a novel neoantigen and a promising therapeutic target in gastric cancer. HDSP is not a classical receptor, enzyme, or transcription factor but a microprotein derived from a long non-coding RNA. No approved drugs directly target HDSP as of the most recent reports, but the molecule is under investigation for peptide-based immunotherapies. The gene does not encode a conventional protein but represents a new therapeutic paradigm: functional micropeptides from lncRNAs.

Other names

HOXA10-HOXA9HOXA10-HOXA9 readthroughHDSP

Peptide vaccine/neoantigen (immunotherapeutic); Inhibition of TRIM25-mediated ubiquitination leading to MECOM protein stabilization; Activation of SPINK1-EGFR signaling pathway