The low-complexity domains of the KMT2D protein regulate histone monomethylation transcription to facilitate pancreatic cancer progression

Abstract Background Liquid–liquid phase separation (LLPS) within the nucleus is directly linked to driving gene expression through transcriptional complexes. Histone lysine methyltransferase 2D (KMT2D) is widely present in many cancers. It is known to epigenetically stimulate the expression of genes...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Weihan Li, Lei Wu, Hui Jia, Zenghua Lin, Renhao Zhong, Yukun Li, Chenwei Jiang, Shifan Liu, Xiaorong Zhou, Erhao Zhang
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	KMT2D Low-complexity domain Liquid–liquid phase separation H3K4 monomethylation Epigenetic therapy Cytology QH573-671
Acceso en línea:	https://doaj.org/article/038d2305d1e04610b86c719a9dd57d75
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:038d2305d1e04610b86c719a9dd57d75
record_format	dspace
spelling	oai:doaj.org-article:038d2305d1e04610b86c719a9dd57d752021-11-14T12:10:09ZThe low-complexity domains of the KMT2D protein regulate histone monomethylation transcription to facilitate pancreatic cancer progression10.1186/s11658-021-00292-71425-81531689-1392https://doaj.org/article/038d2305d1e04610b86c719a9dd57d752021-11-01T00:00:00Zhttps://doi.org/10.1186/s11658-021-00292-7https://doaj.org/toc/1425-8153https://doaj.org/toc/1689-1392Abstract Background Liquid–liquid phase separation (LLPS) within the nucleus is directly linked to driving gene expression through transcriptional complexes. Histone lysine methyltransferase 2D (KMT2D) is widely present in many cancers. It is known to epigenetically stimulate the expression of genes associated with tumorigenesis and metastasis. Our analyses show that KMT2D possesses two distinct low-complexity domains (LCDs) capable of driving the assembly of membrane-less condensates. The dependence of the mechanisms underlying monomethylation of H3K4 on the LLPS microenvironment derived from KMT2D LCDs is unclear in tumor. Methods KMT2D LCD-depletion cells were used to investigate tumor cell proliferation, apoptosis, and migration. We identified some core proteins, including WDR5, RBBP5, and ASH2L, which are involved in the KMT2D-associated catalytic complex in KMT2D LCD-deficient cells to further elucidate the mechanism that decreases monomethylation of H3K4. We also evaluated the viability of KMT2D LCD-deficient cells in vivo. Finally, using 1,6-hexanediol (HD), an inhibitor of LLPS, we determined cell activities associated with KMT2D function in wild-type PANC-1 cells. Results Without the LLPS microenvironment in KMT2D LCD-deficient cells or wild-type PANC-1 cells treated with HD, the WDR5 protein was significantly less stable and the protein–protein interactions between the components of the KMT2D–enzyme complex were attenuated, impairing the formation of the complex. Moreover, with the decrease in H3K4me1 level at enhancers, transcription factors such as LIFR and KLF4 were markedly downregulated, effectively inhibiting tumor progression. In xenograft tumor models, PANC-1 cells lacking the KMT2D LCDs showed effectively suppressed tumor growth compared to normal cells. Conclusions Our data indicate that the two low-complexity domains of the KMT2D protein could form a stable LLPS microenvironment, promoting the KMT2D catalysis of H3K4 monomethylation through stabilization of the WDR5 protein and KMT2D–enzyme complex. Therefore, finding ways to regulate the LLPS microenvironment will be benefitial for new cancer treatment strategies.Weihan LiLei WuHui JiaZenghua LinRenhao ZhongYukun LiChenwei JiangShifan LiuXiaorong ZhouErhao ZhangBMCarticleKMT2DLow-complexity domainLiquid–liquid phase separationH3K4 monomethylationEpigenetic therapyCytologyQH573-671ENCellular & Molecular Biology Letters, Vol 26, Iss 1, Pp 1-20 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	KMT2D Low-complexity domain Liquid–liquid phase separation H3K4 monomethylation Epigenetic therapy Cytology QH573-671
spellingShingle	KMT2D Low-complexity domain Liquid–liquid phase separation H3K4 monomethylation Epigenetic therapy Cytology QH573-671 Weihan Li Lei Wu Hui Jia Zenghua Lin Renhao Zhong Yukun Li Chenwei Jiang Shifan Liu Xiaorong Zhou Erhao Zhang The low-complexity domains of the KMT2D protein regulate histone monomethylation transcription to facilitate pancreatic cancer progression
description	Abstract Background Liquid–liquid phase separation (LLPS) within the nucleus is directly linked to driving gene expression through transcriptional complexes. Histone lysine methyltransferase 2D (KMT2D) is widely present in many cancers. It is known to epigenetically stimulate the expression of genes associated with tumorigenesis and metastasis. Our analyses show that KMT2D possesses two distinct low-complexity domains (LCDs) capable of driving the assembly of membrane-less condensates. The dependence of the mechanisms underlying monomethylation of H3K4 on the LLPS microenvironment derived from KMT2D LCDs is unclear in tumor. Methods KMT2D LCD-depletion cells were used to investigate tumor cell proliferation, apoptosis, and migration. We identified some core proteins, including WDR5, RBBP5, and ASH2L, which are involved in the KMT2D-associated catalytic complex in KMT2D LCD-deficient cells to further elucidate the mechanism that decreases monomethylation of H3K4. We also evaluated the viability of KMT2D LCD-deficient cells in vivo. Finally, using 1,6-hexanediol (HD), an inhibitor of LLPS, we determined cell activities associated with KMT2D function in wild-type PANC-1 cells. Results Without the LLPS microenvironment in KMT2D LCD-deficient cells or wild-type PANC-1 cells treated with HD, the WDR5 protein was significantly less stable and the protein–protein interactions between the components of the KMT2D–enzyme complex were attenuated, impairing the formation of the complex. Moreover, with the decrease in H3K4me1 level at enhancers, transcription factors such as LIFR and KLF4 were markedly downregulated, effectively inhibiting tumor progression. In xenograft tumor models, PANC-1 cells lacking the KMT2D LCDs showed effectively suppressed tumor growth compared to normal cells. Conclusions Our data indicate that the two low-complexity domains of the KMT2D protein could form a stable LLPS microenvironment, promoting the KMT2D catalysis of H3K4 monomethylation through stabilization of the WDR5 protein and KMT2D–enzyme complex. Therefore, finding ways to regulate the LLPS microenvironment will be benefitial for new cancer treatment strategies.
format	article
author	Weihan Li Lei Wu Hui Jia Zenghua Lin Renhao Zhong Yukun Li Chenwei Jiang Shifan Liu Xiaorong Zhou Erhao Zhang
author_facet	Weihan Li Lei Wu Hui Jia Zenghua Lin Renhao Zhong Yukun Li Chenwei Jiang Shifan Liu Xiaorong Zhou Erhao Zhang
author_sort	Weihan Li
title	The low-complexity domains of the KMT2D protein regulate histone monomethylation transcription to facilitate pancreatic cancer progression
title_short	The low-complexity domains of the KMT2D protein regulate histone monomethylation transcription to facilitate pancreatic cancer progression
title_full	The low-complexity domains of the KMT2D protein regulate histone monomethylation transcription to facilitate pancreatic cancer progression
title_fullStr	The low-complexity domains of the KMT2D protein regulate histone monomethylation transcription to facilitate pancreatic cancer progression
title_full_unstemmed	The low-complexity domains of the KMT2D protein regulate histone monomethylation transcription to facilitate pancreatic cancer progression
title_sort	low-complexity domains of the kmt2d protein regulate histone monomethylation transcription to facilitate pancreatic cancer progression
publisher	BMC
publishDate	2021
url	https://doaj.org/article/038d2305d1e04610b86c719a9dd57d75
work_keys_str_mv	AT weihanli thelowcomplexitydomainsofthekmt2dproteinregulatehistonemonomethylationtranscriptiontofacilitatepancreaticcancerprogression AT leiwu thelowcomplexitydomainsofthekmt2dproteinregulatehistonemonomethylationtranscriptiontofacilitatepancreaticcancerprogression AT huijia thelowcomplexitydomainsofthekmt2dproteinregulatehistonemonomethylationtranscriptiontofacilitatepancreaticcancerprogression AT zenghualin thelowcomplexitydomainsofthekmt2dproteinregulatehistonemonomethylationtranscriptiontofacilitatepancreaticcancerprogression AT renhaozhong thelowcomplexitydomainsofthekmt2dproteinregulatehistonemonomethylationtranscriptiontofacilitatepancreaticcancerprogression AT yukunli thelowcomplexitydomainsofthekmt2dproteinregulatehistonemonomethylationtranscriptiontofacilitatepancreaticcancerprogression AT chenweijiang thelowcomplexitydomainsofthekmt2dproteinregulatehistonemonomethylationtranscriptiontofacilitatepancreaticcancerprogression AT shifanliu thelowcomplexitydomainsofthekmt2dproteinregulatehistonemonomethylationtranscriptiontofacilitatepancreaticcancerprogression AT xiaorongzhou thelowcomplexitydomainsofthekmt2dproteinregulatehistonemonomethylationtranscriptiontofacilitatepancreaticcancerprogression AT erhaozhang thelowcomplexitydomainsofthekmt2dproteinregulatehistonemonomethylationtranscriptiontofacilitatepancreaticcancerprogression AT weihanli lowcomplexitydomainsofthekmt2dproteinregulatehistonemonomethylationtranscriptiontofacilitatepancreaticcancerprogression AT leiwu lowcomplexitydomainsofthekmt2dproteinregulatehistonemonomethylationtranscriptiontofacilitatepancreaticcancerprogression AT huijia lowcomplexitydomainsofthekmt2dproteinregulatehistonemonomethylationtranscriptiontofacilitatepancreaticcancerprogression AT zenghualin lowcomplexitydomainsofthekmt2dproteinregulatehistonemonomethylationtranscriptiontofacilitatepancreaticcancerprogression AT renhaozhong lowcomplexitydomainsofthekmt2dproteinregulatehistonemonomethylationtranscriptiontofacilitatepancreaticcancerprogression AT yukunli lowcomplexitydomainsofthekmt2dproteinregulatehistonemonomethylationtranscriptiontofacilitatepancreaticcancerprogression AT chenweijiang lowcomplexitydomainsofthekmt2dproteinregulatehistonemonomethylationtranscriptiontofacilitatepancreaticcancerprogression AT shifanliu lowcomplexitydomainsofthekmt2dproteinregulatehistonemonomethylationtranscriptiontofacilitatepancreaticcancerprogression AT xiaorongzhou lowcomplexitydomainsofthekmt2dproteinregulatehistonemonomethylationtranscriptiontofacilitatepancreaticcancerprogression AT erhaozhang lowcomplexitydomainsofthekmt2dproteinregulatehistonemonomethylationtranscriptiontofacilitatepancreaticcancerprogression
_version_	1718429387050713088

The low-complexity domains of the KMT2D protein regulate histone monomethylation transcription to facilitate pancreatic cancer progression

Ejemplares similares