m6A modification confers thermal vulnerability to HPV E7 oncotranscripts via reverse regulation of its reader protein IGF2BP1 upon heat stress

Lingfang Wang; Guankai Zhan; Yasen Maimaitiyiming; Yingfeng Su; Shitong Lin; Jinfeng Liu; Kunhui Su; Jiebo Lin; Shizhen Shen; Wentao He; Fenfen Wang; Jiafeng Chen; Siqi Sun; Yite Xue; Jiaxin Gu; Xiaojing Chen; Jian Zhang; Lu Zhang; Qianqian Wang; Kao Jung Chang; Shih Hwa Chiou; Mikael Björklund; Hua Naranmandura; Xiaodong Cheng; Chih Hung Hsu

doi:10.1016/j.celrep.2022.111546

m⁶A modification confers thermal vulnerability to HPV E7 oncotranscripts via reverse regulation of its reader protein IGF2BP1 upon heat stress

Lingfang Wang, Guankai Zhan, Yasen Maimaitiyiming, Yingfeng Su, Shitong Lin, Jinfeng Liu, Kunhui Su, Jiebo Lin, Shizhen Shen, Wentao He, Fenfen Wang, Jiafeng Chen, Siqi Sun, Yite Xue, Jiaxin Gu, Xiaojing Chen, Jian Zhang, Lu Zhang, Qianqian Wang, Kao Jung ChangShih Hwa Chiou, Mikael Björklund, Hua Naranmandura^*, Xiaodong Cheng, Chih Hung Hsu

^*此作品的通信作者

研究成果: Article › 同行評審

4 引文斯高帕斯（Scopus）

摘要

Human papillomavirus (HPV)-induced carcinogenesis critically depends on the viral early protein 7 (E7), making E7 an attractive therapeutic target. Here, we report that the E7 messenger RNA (mRNA)-containing oncotranscript complex can be selectively targeted by heat treatment. In HPV-infected cells, viral E7 mRNA is modified by N⁶-methyladenosine (m⁶A) and stabilized by IGF2BP1, a cellular m⁶A reader. Heat treatment downregulates E7 mRNA and protein by destabilizing IGF2BP1 without the involvement of canonical heat-shock proteins and reverses HPV-associated carcinogenesis in vitro and in vivo. Mechanistically, heat treatment promotes IGF2BP1 aggregation only in the presence of m⁶A-modified E7 mRNA to form distinct heat-induced m⁶A E7 mRNA-IGF2BP1 granules, which are resolved by the ubiquitin-proteasome system. Collectively, our results not only show a mutual regulation between m⁶A RNA and its reader but also provide a heat-treatment-based therapeutic strategy for HPV-associated malignancies by specifically downregulating E7 mRNA-IGF2BP1 oncogenic complex.

原文	English
文章編號	111546
期刊	Cell Reports
卷	41
發行號	4
DOIs	https://doi.org/10.1016/j.celrep.2022.111546
出版狀態	Published - 25 10月 2022

UN SDG

此研究成果有助於以下永續發展目標

存取文件

10.1016/j.celrep.2022.111546

其它文件與鏈接

Link to publication in Scopus

引用此

Wang, L., Zhan, G., Maimaitiyiming, Y., Su, Y., Lin, S., Liu, J., Su, K., Lin, J., Shen, S., He, W., Wang, F., Chen, J., Sun, S., Xue, Y., Gu, J., Chen, X., Zhang, J., Zhang, L., Wang, Q., ... Hsu, C. H. (2022). m⁶A modification confers thermal vulnerability to HPV E7 oncotranscripts via reverse regulation of its reader protein IGF2BP1 upon heat stress. Cell Reports, 41(4), Article 111546. https://doi.org/10.1016/j.celrep.2022.111546

@article{698868a3387f4e2ea84a5336252e679c,

title = "m6A modification confers thermal vulnerability to HPV E7 oncotranscripts via reverse regulation of its reader protein IGF2BP1 upon heat stress",

abstract = "Human papillomavirus (HPV)-induced carcinogenesis critically depends on the viral early protein 7 (E7), making E7 an attractive therapeutic target. Here, we report that the E7 messenger RNA (mRNA)-containing oncotranscript complex can be selectively targeted by heat treatment. In HPV-infected cells, viral E7 mRNA is modified by N6-methyladenosine (m6A) and stabilized by IGF2BP1, a cellular m6A reader. Heat treatment downregulates E7 mRNA and protein by destabilizing IGF2BP1 without the involvement of canonical heat-shock proteins and reverses HPV-associated carcinogenesis in vitro and in vivo. Mechanistically, heat treatment promotes IGF2BP1 aggregation only in the presence of m6A-modified E7 mRNA to form distinct heat-induced m6A E7 mRNA-IGF2BP1 granules, which are resolved by the ubiquitin-proteasome system. Collectively, our results not only show a mutual regulation between m6A RNA and its reader but also provide a heat-treatment-based therapeutic strategy for HPV-associated malignancies by specifically downregulating E7 mRNA-IGF2BP1 oncogenic complex.",

keywords = "cervical cancer, CP: Cancer, CP: Molecular biology, heat stress, HPV, human papillomavirus E7 oncotranscripts, hyperthermia, m6A, m6A reader IGF2BP1, N6-methyladenosine, phase separation, protein degradation",

author = "Lingfang Wang and Guankai Zhan and Yasen Maimaitiyiming and Yingfeng Su and Shitong Lin and Jinfeng Liu and Kunhui Su and Jiebo Lin and Shizhen Shen and Wentao He and Fenfen Wang and Jiafeng Chen and Siqi Sun and Yite Xue and Jiaxin Gu and Xiaojing Chen and Jian Zhang and Lu Zhang and Qianqian Wang and Chang, {Kao Jung} and Chiou, {Shih Hwa} and Mikael Bj{\"o}rklund and Hua Naranmandura and Xiaodong Cheng and Hsu, {Chih Hung}",

note = "Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = oct,

day = "25",

doi = "10.1016/j.celrep.2022.111546",

language = "English",

volume = "41",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "4",

}

Wang, L, Zhan, G, Maimaitiyiming, Y, Su, Y, Lin, S, Liu, J, Su, K, Lin, J, Shen, S, He, W, Wang, F, Chen, J, Sun, S, Xue, Y, Gu, J, Chen, X, Zhang, J, Zhang, L, Wang, Q, Chang, KJ, Chiou, SH, Björklund, M, Naranmandura, H, Cheng, X & Hsu, CH 2022, 'm⁶A modification confers thermal vulnerability to HPV E7 oncotranscripts via reverse regulation of its reader protein IGF2BP1 upon heat stress', Cell Reports, 卷 41, 編號 4, 111546. https://doi.org/10.1016/j.celrep.2022.111546

TY - JOUR

T1 - m6A modification confers thermal vulnerability to HPV E7 oncotranscripts via reverse regulation of its reader protein IGF2BP1 upon heat stress

AU - Wang, Lingfang

AU - Zhan, Guankai

AU - Maimaitiyiming, Yasen

AU - Su, Yingfeng

AU - Lin, Shitong

AU - Liu, Jinfeng

AU - Su, Kunhui

AU - Lin, Jiebo

AU - Shen, Shizhen

AU - He, Wentao

AU - Wang, Fenfen

AU - Chen, Jiafeng

AU - Sun, Siqi

AU - Xue, Yite

AU - Gu, Jiaxin

AU - Chen, Xiaojing

AU - Zhang, Jian

AU - Zhang, Lu

AU - Wang, Qianqian

AU - Chang, Kao Jung

AU - Chiou, Shih Hwa

AU - Björklund, Mikael

AU - Naranmandura, Hua

AU - Cheng, Xiaodong

AU - Hsu, Chih Hung

PY - 2022/10/25

Y1 - 2022/10/25

N2 - Human papillomavirus (HPV)-induced carcinogenesis critically depends on the viral early protein 7 (E7), making E7 an attractive therapeutic target. Here, we report that the E7 messenger RNA (mRNA)-containing oncotranscript complex can be selectively targeted by heat treatment. In HPV-infected cells, viral E7 mRNA is modified by N6-methyladenosine (m6A) and stabilized by IGF2BP1, a cellular m6A reader. Heat treatment downregulates E7 mRNA and protein by destabilizing IGF2BP1 without the involvement of canonical heat-shock proteins and reverses HPV-associated carcinogenesis in vitro and in vivo. Mechanistically, heat treatment promotes IGF2BP1 aggregation only in the presence of m6A-modified E7 mRNA to form distinct heat-induced m6A E7 mRNA-IGF2BP1 granules, which are resolved by the ubiquitin-proteasome system. Collectively, our results not only show a mutual regulation between m6A RNA and its reader but also provide a heat-treatment-based therapeutic strategy for HPV-associated malignancies by specifically downregulating E7 mRNA-IGF2BP1 oncogenic complex.

AB - Human papillomavirus (HPV)-induced carcinogenesis critically depends on the viral early protein 7 (E7), making E7 an attractive therapeutic target. Here, we report that the E7 messenger RNA (mRNA)-containing oncotranscript complex can be selectively targeted by heat treatment. In HPV-infected cells, viral E7 mRNA is modified by N6-methyladenosine (m6A) and stabilized by IGF2BP1, a cellular m6A reader. Heat treatment downregulates E7 mRNA and protein by destabilizing IGF2BP1 without the involvement of canonical heat-shock proteins and reverses HPV-associated carcinogenesis in vitro and in vivo. Mechanistically, heat treatment promotes IGF2BP1 aggregation only in the presence of m6A-modified E7 mRNA to form distinct heat-induced m6A E7 mRNA-IGF2BP1 granules, which are resolved by the ubiquitin-proteasome system. Collectively, our results not only show a mutual regulation between m6A RNA and its reader but also provide a heat-treatment-based therapeutic strategy for HPV-associated malignancies by specifically downregulating E7 mRNA-IGF2BP1 oncogenic complex.

KW - cervical cancer

KW - CP: Cancer

KW - CP: Molecular biology

KW - heat stress

KW - HPV

KW - human papillomavirus E7 oncotranscripts

KW - hyperthermia

KW - m6A

KW - m6A reader IGF2BP1

KW - N6-methyladenosine

KW - phase separation

KW - protein degradation

UR - http://www.scopus.com/inward/record.url?scp=85140333403&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2022.111546

DO - 10.1016/j.celrep.2022.111546

M3 - Article

C2 - 36288717

AN - SCOPUS:85140333403

SN - 2211-1247

VL - 41

JO - Cell Reports

JF - Cell Reports

IS - 4

M1 - 111546

ER -

m6A modification confers thermal vulnerability to HPV E7 oncotranscripts via reverse regulation of its reader protein IGF2BP1 upon heat stress

摘要

UN SDG

存取文件

其它文件與鏈接

指紋

引用此

m⁶A modification confers thermal vulnerability to HPV E7 oncotranscripts via reverse regulation of its reader protein IGF2BP1 upon heat stress