Novel Tumor Suppressor PMM1 Suppresses Oral Cancer Growth through Activation Unfolding Protein Response Activator EGR1

Abstract

Protein glycosylation is the common post‐translational modification in the mammalian cells. More than half proteins have their own glycosylation which increasing the protein diversity and complexity or maintaining protein stability. N‐glycosylation is a quality control marker of protein folding. Aberrant n‐glycosylation usually cause unfolding protein response and endoplasmic reticulum stress. Here, we find phosphomannomutase 1 (PMM1), which converts initiation molecule in n‐glycosylation to mannose‐1‐phosphate, serves as a tumor suppressor gene in oral squamous cell carcinoma (OSCC). PMM1 peptide sequence and enzymatic substrate are highly similar to PMM2. However, we found PMM1 might have an opposite cancer progression effect in public prognosis analysis. Ectopic wildtype PMM1 expression suppressed in vitro cancer cell proliferation, but not in the catalytic domain death PMM1‐R150H clone. Furthermore, wildtype PMM1 also suppressed the in vivo OSCC cell growth in the Nod‐SCID immunodeficient mice. Transcriptome analysis by cDNA microarray and ingenuity pathway analysis revealed that PMM1 stimulated early growth response protein 1 (EGR1) pathway activation. As we known, EGR1 is a tumor suppressor and the master activator in unfolding protein response. Our study suggests that PMM1 is a gatekeeper in cellular protein folding and OSCC tumor suppressor through regulating EGR1 expression. This study provides new insights into an important mechanism for n‐glycosylation and protein folding in oral carcinoma, which may be helpful for biomarker and therapeutic development in the future.