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

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

doi:10.1038/s41396-021-01119-1

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

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

Department of Medicine

Research output: Contribution to journal › Article › peer-review

53 Scopus citations

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.

Original language	English
Pages (from-to)	1205-1221
Number of pages	17
Journal	ISME Journal
Volume	16
Issue number	5
DOIs	https://doi.org/10.1038/s41396-021-01119-1
State	Published - May 2022

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Ryu, T. Y., Kim, K., Han, T. S., Lee, M. O., Lee, J., Choi, J., Jung, K. B., Jeong, E. J., An, D. M., Jung, C. R., Lim, J. H., Jung, J., Park, K., Lee, M. S., Kim, M. Y., Oh, S. J., Hur, K., Hamamoto, R., Park, D. S., ... Cho, H. S. (2022). Human gut-microbiome-derived propionate coordinates proteasomal degradation via HECTD2 upregulation to target EHMT2 in colorectal cancer. ISME Journal, 16(5), 1205-1221. https://doi.org/10.1038/s41396-021-01119-1

@article{dc4dab5782794c5e8d8cb001641ace5b,

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

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.",

author = "Ryu, {Tae Young} and Kwangho Kim and Han, {Tae Su} and Lee, {Mi Ok} and Jinkwon Lee and Jinhyeon Choi and Jung, {Kwang Bo} and Jeong, {Eun Jeong} and An, {Da Mi} and Jung, {Cho Rok} and Lim, {Jung Hwa} and Jaeeun Jung and Kunhyang Park and Lee, {Moo Seung} and Kim, {Mi Young} and Oh, {Soo Jin} and Keun Hur and Ryuji Hamamoto and Park, {Doo Sang} and Kim, {Dae Soo} and Son, {Mi Young} and Cho, {Hyun Soo}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2022",

month = may,

doi = "10.1038/s41396-021-01119-1",

language = "English",

volume = "16",

pages = "1205--1221",

journal = "ISME Journal",

issn = "1751-7362",

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Ryu, TY, Kim, K, Han, TS, Lee, MO, Lee, J, Choi, J, Jung, KB, Jeong, EJ, An, DM, Jung, CR, Lim, JH, Jung, J, Park, K, Lee, MS, Kim, MY, Oh, SJ, Hur, K, Hamamoto, R, Park, DS, Kim, DS, Son, MY & Cho, HS 2022, 'Human gut-microbiome-derived propionate coordinates proteasomal degradation via HECTD2 upregulation to target EHMT2 in colorectal cancer', ISME Journal, vol. 16, no. 5, pp. 1205-1221. https://doi.org/10.1038/s41396-021-01119-1

TY - JOUR

T1 - Human gut-microbiome-derived propionate coordinates proteasomal degradation via HECTD2 upregulation to target EHMT2 in colorectal cancer

AU - Ryu, Tae Young

AU - Kim, Kwangho

AU - Han, Tae Su

AU - Lee, Mi Ok

AU - Lee, Jinkwon

AU - Choi, Jinhyeon

AU - Jung, Kwang Bo

AU - Jeong, Eun Jeong

AU - An, Da Mi

AU - Jung, Cho Rok

AU - Lim, Jung Hwa

AU - Jung, Jaeeun

AU - Park, Kunhyang

AU - Lee, Moo Seung

AU - Kim, Mi Young

AU - Oh, Soo Jin

AU - Hur, Keun

AU - Hamamoto, Ryuji

AU - Park, Doo Sang

AU - Kim, Dae Soo

AU - Son, Mi Young

AU - Cho, Hyun Soo

PY - 2022/5

Y1 - 2022/5

N2 - 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.

AB - 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.

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U2 - 10.1038/s41396-021-01119-1

DO - 10.1038/s41396-021-01119-1

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SN - 1751-7362

VL - 16

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JF - ISME Journal

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ER -

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

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