LncRNA SNHG17 interacts with LRPPRC to stabilize c-Myc protein and promote G1/S transition and cell proliferation

Jin-Yu Liu,Jin-E Yang,Ya-Jing Chen,Yun-Long Wang,Zhan-Li Chen,Huan-Hui Feng,Shi-Mei Zhuang

doi:10.1038/s41419-021-04238-x

Abstract

Oncogenic c-Myc is a master regulator of G1/S transition. Long non-coding RNAs (lncRNAs) emerge as new regulators of various cell activities. Here, we found that lncRNA SnoRNA Host Gene 17 (SNHG17) was elevated at the early G1-phase of cell cycle. Both gain- and loss-of function studies disclosed that SNHG17 increased c-Myc protein level, accelerated G1/S transition and cell proliferation, and consequently promoted tumor cell growth in vitro and in vivo. Mechanistically, the 1-150-nt of SNHG17 physically interacted with the 1035-1369-aa of leucine rich pentatricopeptide repeat containing (LRPPRC) protein, and disrupting this interaction abrogated the promoting role of SNHG17 in c-Myc expression, G1/S transition, and cell proliferation. The effect of SNHG17 in stimulating cell proliferation was attenuated by silencing c-Myc or LRPPRC. Furthermore, silencing SNHG17 or LRPPRC increased the level of ubiquitylated c-Myc and reduced the stability of c-Myc protein. Analysis of human hepatocellular carcinoma (HCC) tissues revealed that SNHG17, LRPPRC, and c-Myc were significantly upregulated in HCC, and they showed a positive correlation with each other. High level of SNHG17 or LRPPRC was associated with worse survival of HCC patients. These data suggest that SNHG17 may inhibit c-Myc ubiquitination and thus enhance c-Myc level and facilitate proliferation by interacting with LRPPRC. Our findings identify a novel SNHG17-LRPPRC-c-Myc regulatory axis and elucidate its roles in G1/S transition and tumor growth, which may provide potential targets for cancer therapy.

Highlights

The G1 to S phase (G1/S) transition is the key step that drives cell to the division cycle, and it is tightly controlled by the cyclindependent kinase (CDK)-Rb-E2F pathway [1, 2]. c-Myc is a master regulator of cell proliferation via acting as a transcription factor
In an attempt to identify oncogenic Long non-coding RNAs (lncRNAs) that regulate G1/S transition, we screened for the lncRNAs that were differentially expressed during cell cycle progression and found that lncRNA SnoRNA Host Gene 17 (SNHG17) was upregulated at the early G1phase and in various cancer types, including hepatocellular carcinoma (HCC)
We identify an oncogenic lncRNA SNHG17 that is upregulated at the early G1-phase and in various cancer types, including HCC

Summary

INTRODUCTION

The G1 to S phase (G1/S) transition is the key step that drives cell to the division cycle, and it is tightly controlled by the cyclindependent kinase (CDK)-Rb-E2F pathway [1, 2]. c-Myc is a master regulator of cell proliferation via acting as a transcription factor. Recent studies in animal models show that selective small molecules targeting the BET bromodomains-containing proteins that regulate c-Myc activity can downregulate the c-Myc transcriptional signaling, reduce tumor burden, and prolong survival. In an attempt to identify oncogenic lncRNAs that regulate G1/S transition, we screened for the lncRNAs that were differentially expressed during cell cycle progression and found that lncRNA SnoRNA Host Gene 17 (SNHG17) was upregulated at the early G1phase and in various cancer types, including hepatocellular carcinoma (HCC). It increased the stability of c-Myc protein and in turn accelerated G1/S transition and cell proliferation via physically interacting with leucine rich pentatricopeptide repeat containing (LRPPRC) protein. The importance of the SNHG17-LRPPRC-c-Myc axis in G1/S downstream target genes (CDK4, CDK2, cyclin A2) were significantly transition and tumor growth, which may provide potential targets increased in SNHG17-overexpressing cells

RESULTS

DISCUSSION

MATERIALS AND METHODS

Findings

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