RING-finger protein 6 promotes colorectal tumorigenesis by transcriptionally activating SF3B2

Yan Li,Hui Xu,Weilin Li,Yunfei Zhou,Lifu Wang,Jun Yu,Lei Liu,Chi Chun Wong

doi:10.1038/s41388-021-01872-9

Abstract

RNF6 is a RING finger protein with oncogenic potential. In this study, we established colon-specific RNF6 transgenic (tg) mice, and demonstrated that RNF6 overexpression accelerated colorectal carcinogenesis compared to wild-type littermates in a chemically induced colorectal cancer (CRC) model. To understand whether transcriptional activity of RNF6 underlies its oncogenic effect, we performed integrated chromatin immunoprecipitation (ChIP)-sequencing and RNA-sequencing analysis to identify splicing factor 3b subunit 2 (SF3B2) as a potential downstream target of RNF6. RNF6 binds to the SF3B2 promoter and the overexpression of RNF6 activates SF3B2 expression in CRC cells, primary CRC organoids, and RNF6 tg mice. SF3B2 knockout abrogated the tumor promoting effect of RNF6 overexpression, whereas the reexpression of SF3B2 recused cell growth and migration/invasion in RNF6 knockout cells, indicating that SF3B2 is a functional downstream target of RNF6 in CRC. Targeting of RNF6-SF3B2 axis with SF3B2 inhibitor with pladienolide B suppressed the growth of CRC cells with RNF6 overexpression in vitro and in vivo. Moreover, the combination of 5-fluorouracil (5-FU) plus pladienolide B exerted synergistic effects in CRC with high RNF6 expression, leading to tumor regression in xenograft models. These findings indicate that tumor promoting effect of RNF6 is achieved mainly via transcriptional upregulation of SF3B2, and that RNF6-SF3B2 axis is a promising target for CRC therapy.

Highlights

Colorectal cancer (CRC) is one of the most common malignancies worldwide and the third leading cause of cancer deaths [1]
Our results provide compelling evidence that RNF6 overexpression aggravates CRC progression
The majority of RNF proteins are believed to function as E3 ubiquitin ligases, their RING domains can bind to DNA and mediate transcription

Summary

Introduction

Colorectal cancer (CRC) is one of the most common malignancies worldwide and the third leading cause of cancer deaths [1]. Surgical resection remains to be the primary option for CRC treatment; few options are available for patients with distant metastasis. Chemotherapy such as platinum-based drugs and 5-fluorouracil (5-FU) are routinely recommended but their effectiveness is limited by intrinsic drug resistance. There is an urgent need to develop novel therapeutic strategy for CRC. Gene amplification is a hallmark of cancer and is frequently detected in CRC [6]. We identified amplification of RNF6 by whole genome sequencing in CRC specimens, which correlates with its overexpression. Little is known with regards to the potential role of RNF6-mediated transcriptional regulation in tumor development and progression

Methods

Results

Conclusion