HMG-box transcription factor 1: a positive regulator of the G1/S transition through the Cyclin-CDK-CDKI molecular network in nasopharyngeal carcinoma

Shiwei He,Dan Gao Dan Gao,Man Niu,Cijun Shuai,Yancheng Zhong,Bo Xiang,Yanhong Zhou,Sheng Yang,Wei Xiong,Guiyuan Li,Shuping Peng,Haotian Ma,Ming Zhou,Yanru Zhang

doi:10.1038/s41419-017-0175-4

Abstract

HMG-box transcription factor 1 (HBP1) has been reported to be a tumor suppressor in diverse malignant carcinomas. However, our findings provide a conclusion that HBP1 plays a novel role in facilitating nasopharyngeal carcinoma (NPC) growth. The Kaplan–Meier analysis indicates that high expression HBP1 and low miR-29c expression both are negatively correlated with the overall survival rates of NPC patients. HBP1 knockdown inhibits cellular proliferation and growth, and arrested cells in G1 phase rather than affected cell apoptosis via flow cytometry (FCM) analysis. Mechanistically, HBP1 induces the expression of CCND1 and CCND3 levels by binding to their promoters, and binds to CDK4, CDK6 and p16INK4A promoters while not affects their expression levels. CCND1 and CCND3 promote CCND1-CDK4, CCND3-CDK6, and CDK2-CCNE1 complex formation, thus, E2F-1 and DP-1 are activated to accelerate the G1/S transition in the cell cycle. MiR-29c is down-regulated and correlated with NPC tumorigenesis and progression. Luciferase assays confirms that miR-29c binds to the 3′ untranslated region (3′-UTR) of HBP1. Introduction of pre-miR-29c decreased HBP1 mRNA and protein levels. Therefore, the high endogenous HBP1 expression might be attributed to the low levels of endogenous miR-29c in NPC. In addition, HBP1 knockdown and miR-29c agomir administration both decrease xenograft growth in nude mice in vivo. It is firstly reported that HBP1 knockdown inhibited the proliferation and metastasis of NPC, which indicates that HBP1 functions as a non-tumor suppressor gene in NPC. This study provides a novel potential target for the prevention of and therapies for NPC.

Highlights

Nasopharyngeal carcinoma (NPC) is the most common cancer originating in the nasopharynx and predominant in Southeast Asia and Africa, especially in South China[1,2]
HMG-box transcription factor 1 (HBP1) is highly expressed in NPC tissues or cell lines It has been reported that miR-29c is a suppressor and expressed at a very low levels in various tumors and down-regulated in NPC cell lines[10]
Immunofluorescence results suggested that HBP1 exhibited higher fluorescence intensity in these HK1, HNE1, and CNE2 cells than in normal nasopharyngeal epithelial cells (NP69) and mainly located in the cell nucleus, while in situ hybridization results revealed that miR-29c was distributed in both the cytoplasm and nucleus at low miRNA levels (Fig. 1b)

Summary

Introduction

Nasopharyngeal carcinoma (NPC) is the most common cancer originating in the nasopharynx and predominant in Southeast Asia and Africa, especially in South China[1,2]. Official journal of the Cell Death Differentiation Association He et al Cell Death and Disease (2018)9:100 factor 1) is another tentative target gene of miR-29c. HBP1 is a transcription factor that contains a HMG-box (DNA-binding domain). It was firstly cloned from rat brains, and its functions were initially confirmed in cell differentiation and premature senescence[11,12,13]. HBP1 regulates the timing of neuronal differentiation through downstream genes such as cyclin D1 (CCND1), a downstream signal molecule in the Wnt signaling pathway. HBP1 inhibits the Wnt/β-catenin signaling pathway by inhibiting the activity of LEF/TCFs and preventing β-catenin from being transported into the nucleus and inhibits the growth of HCT116 and Caco-2A colon cancer cells[18,19,20,21]. The role of HBP1 in NPC has not been defined yet

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