Human gut-microbiome-derived propionate coordinates proteasomal degradation via HECTD2 upregulation to target EHMT2 in colorectal cancer

Tae Young Ryu,Da Mi An,Jung Hwa Lim,Kwang Bo Jung,Kwang‐Ho Kim ,Jaeeun Jung,Dae‐Soo Kim ,Tae-Su Han,Kunhyang Park,Jinhyeon Choi,Eun-Jeong Jeong,Doo-Sang Park,Ryuji Hamamoto,Mi‐Ok Lee ,Jinkwon Lee,Cho‐Rok Jung ,Soo Jin Oh,Miyoung Kim ,Keun Hur,Mi‐Young Son ,Hyun Soo Cho

doi:10.1038/s41396-021-01119-1

Abstract

The human microbiome plays an essential role in the human immune system, food digestion, and protection from harmful bacteria by colonizing the human intestine. Recently, although the human microbiome affects colorectal cancer (CRC) treatment, the mode of action between the microbiome and CRC remains unclear. This study showed that propionate suppressed CRC growth by promoting the proteasomal degradation of euchromatic histone-lysine N-methyltransferase 2 (EHMT2) through HECT domain E3 ubiquitin protein ligase 2 (HECTD2) upregulation. In addition, EHMT2 downregulation reduced the H3K9me2 level on the promoter region of tumor necrosis factor α-induced protein 1 (TNFAIP1) as a novel direct target of EHMT2. Subsequently, TNFAIP1 upregulation induced the apoptosis of CRC cells. Furthermore, using Bacteroides thetaiotaomicron culture medium, we confirmed EHMT2 downregulation via upregulation of HECTD2 and TNFAIP1 upregulation. Finally, we observed the synergistic effect of propionate and an EHMT2 inhibitor (BIX01294) in 3D spheroid culture models. Thus, we suggest the anticancer effects of propionate and EHMT2 as therapeutic targets for colon cancer treatment and may provide the possibility for the synergistic effects of an EHMT2 inhibitor and microbiome in CRC treatment.

Highlights

IntroductionChemotherapy (5-fluorouracil (5-FU) and oxaliplatin) and targeted therapy (cetuximab and bevacizumab) are used to treat this disease, new therapeutic methods are needed to reduce the side effects and increase the success rate of Colorectal cancer (CRC) treatment [1,2,3]
Colorectal cancer (CRC) is a commonly diagnosed cancer worldwide
Western blot analysis demonstrated that the levels of cleaved PARP were increased in HCT116 and LS174T cells treated with Sodium propionate (SP) (Fig. 1C)

Summary

Introduction

Chemotherapy (5-fluorouracil (5-FU) and oxaliplatin) and targeted therapy (cetuximab and bevacizumab) are used to treat this disease, new therapeutic methods are needed to reduce the side effects and increase the success rate of CRC treatment [1,2,3]. The human microbiome, including metabolites and the microbiome, has uncovered alternative new CRC treatments [4,5,6]. The microbiome mainly colonizes the large intestine, promotes food digestion, regulates the human immune system, produces vitamins (B12, K, riboflavin), and protects against disease-related bacteria [7,8,9]. In colon cancer, we reported that propionate suppresses CRC growth by downregulating protein arginine N-methyltransferase 1 (PRMT1) expression, and PRMT1 reduction induced cell apoptosis by controlling the mTOR pathway [12]. The mode of action (MOA) of propionate for CRC suppression remains incompletely understood, regarding epigenetics

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Results

Conclusion