Hematological and neurological expressed 1 (HN1) activates c‐Myc signaling by inhibiting ubiquitin‐mediated proteasomal degradation of c‐Myc in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) has a poor prognosis due to the usually advanced stage at diagnosis. Sustained activation of the MYC oncogene is implicated in the development of HCC; however, the molecular mechanisms of MYC deregulation in HCC are poorly understood. Here, real-time PCR and western blotting were used to measure the expression of hematological and neurological expressed 1 (HN1) in HCC cells. Expression of HN1 and MYC in clinical specimens was analyzed using immunohistochemistry. The role of HN1 in HCC proliferation, migration, and invasion was explored in vitro and in vivo. MYC expression was measured using realtime PCR and western blotting. MYC transcriptional activity was assessed using a luciferase reporter system. Expression of MYC target genes was quantified using real-time PCR. Protein interaction between MYC and HN1 was assessed using co-immunoprecipitation and western blotting. We identified HN1 as a novel regulatory factor of the glycogen synthase kinase (GSK) 3β-MYC axis. HN1 expression is elevated in liver tumor tissues and cells, and significantly correlates with poor survival in HCC patients. Upregulation of HN1 promotes, and silencing of HN1 represses, the proliferation and metastasis of liver cancer cells in vitro and in vivo. Moreover, our results demonstrate that HN1 sustains stabilization and persistent activity of MYC via interaction with GSK3β in HCC. Importantly, the tumor-promoting effects of HN1 on HCC cells were attenuated by suppressing MYC. In conclusion, constitutive activation of MYC by HN1 promotes the progression of HCC; therefore, HN1 might be a novel therapeutic target for HCC.

HN1 Is Enriched in the S-Phase, Phosphorylated in Mitosis, and Contributes to Cyclin B1 Degradation in Prostate Cancer Cells

“…HN1 levels fluctuated in the cell cycle, remaining enriched in the S phase and went down after the S phase until the end of G1 with a transition into a phosphorylated form only appearing in mitosis (Figure 1) with potential upstream kinases as GSK3β and Cdk1 (Figure 1). HN1 has been shown as a regulator of the GSK3β signaling pathway previously [9,37]; the inhibition of p-HN1 upon Cdk1i and pan-Cdki treatments implies that HN1 is involved in pathways regulated via Cyclin-dependent kinases (CDKs). The CDK1 regulation of HN1 should be explored further.…”

“…HN1 is upregulated in Hepatocellular carcinoma [36,37,52,53], promotes anaplastic thyroid carcinoma [54], and metastases in Cervical carcinoma [55]. HN1 expression has been associated with MYC, where HN1 overexpression was linked with increased migration and invasiveness in Breast cancer [56].…”