MYC-regulated long non-coding RNA SNHG1 controls S-phase kinase-associated protein 2-mediated p21 protein stability...

Long non-coding RNA SNHG1 has been implicated in hepatocellular carcinoma progression; however, how endocrine signaling regulates SNHG1-mediated ubiquitin-dependent protein turnover remains incompletely understood. We investigated whether thyroid hormone receptor signaling suppresses HCC progression through the MYC-SNHG1-SKP2-p21 axis. SNHG1 was frequently upregulated in HCC tissues and associated with aggressive clinicopathological features and unfavorable outcomes. In tumor specimens from our clinical HCC cohort and TCGA-LIHC tumors, THRB expression was inversely associated with SNHG1 expression. In TCGA-LIHC, combined THRB-low/SNHG1-high expression was associated with poorer survival. Functionally, SNHG1 promoted HCC cell proliferation, sphere formation, and invasion, whereas SNHG1 depletion suppressed these phenotypes. Mechanistically, thyroid hormone receptor β activation suppressed MYC expression and reduced SNHG1 levels. Promoter reporter and ChIP-qPCR analyses showed that TRβ occupied the MYC promoter region and that T3 reduced MYC promoter activity. MYC restoration maintained higher SNHG1 expression under T3 treatment, supporting MYC as an intermediary linking TRβ activation to SNHG1 repression. SNHG1 enhanced SKP2 expression and SKP2 mRNA stability, at least partly through a miR-340-5p-associated post-transcriptional mechanism. Increased SKP2 promoted ubiquitin-mediated degradation of p21 without markedly altering CDKN1A mRNA expression. Conversely, SKP2 knockdown attenuated SNHG1-induced p21 ubiquitination, proliferation, and invasion, whereas SKP2 re-expression partially restored these phenotypes in SNHG1-depleted cells. In xenograft models, hyperthyroid conditions reduced tumor growth and SKP2 expression while increasing p21 protein levels, and SNHG1 overexpression partially reversed these effects. Collectively, these findings support a TH/TRβ-MYC-SNHG1-SKP2-p21 regulatory axis linking endocrine signaling to lncRNA-mediated control of ubiquitin-dependent protein stability in HCC.