Super-enhancer trapping by the nuclear pore via intrinsically disordered regions of proteins in squamous cell carcinoma cells

Masaharu Hazawa; Dini Kurnia Ikliptikawati; Yuki Iwashima; De-Chen Lin; Yuan Jiang; Yujia Qiu; Kei Makiyama; Koki Matsumoto; Akiko Kobayashi; Goro Nishide; Lim Keesiang; Hironori Yoshino; Toshinari Minamoto; Takeshi Suzuki; Isao Kobayashi; Makiko Meguro-Horike; Yan-Yi Jiang; Takumi Nishiuchi; Hiroki Konno; H Phillip Koeffler; Kazuyoshi Hosomichi; Atsushi Tajima; Shin-Ichi Horike; Richard W Wong

doi:10.1016/j.chembiol.2023.10.005

Super-enhancer trapping by the nuclear pore via intrinsically disordered regions of proteins in squamous cell carcinoma cells

Cell Chem Biol. 2024 Apr 18;31(4):792-804.e7. doi: 10.1016/j.chembiol.2023.10.005. Epub 2023 Nov 3.

Authors

Masaharu Hazawa¹, Dini Kurnia Ikliptikawati², Yuki Iwashima³, De-Chen Lin⁴, Yuan Jiang⁵, Yujia Qiu⁶, Kei Makiyama⁷, Koki Matsumoto⁷, Akiko Kobayashi², Goro Nishide⁶, Lim Keesiang⁶, Hironori Yoshino⁸, Toshinari Minamoto⁹, Takeshi Suzuki¹⁰, Isao Kobayashi¹¹, Makiko Meguro-Horike¹², Yan-Yi Jiang⁵, Takumi Nishiuchi¹³, Hiroki Konno⁶, H Phillip Koeffler¹⁴, Kazuyoshi Hosomichi¹⁵, Atsushi Tajima¹⁶, Shin-Ichi Horike¹⁷, Richard W Wong¹⁸

Affiliations

¹ Cell-Bionomics Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan; WPI Nano Life Science Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan; Faculty of Biological Science and Technology, Institute of Science and Engineering, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan; Laboratory of molecular cell biology, School of Natural System, Institute of Science and Engineering, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan. Electronic address: [email protected].
² Cell-Bionomics Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
³ Laboratory of molecular cell biology, School of Natural System, Institute of Science and Engineering, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
⁴ Herman Ostrow School of Dentistry, Center for Craniofacial Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, Los Angeles, CA, USA.
⁵ Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, P.R.China; University of Science and Technology of China, Hefei 230026, P.R.China.
⁶ WPI Nano Life Science Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
⁷ Division of Transdisciplinary Sciences, Graduate School of Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
⁸ Department of Radiation Science, Hirosaki University Graduate School of Health Sciences, Hirosaki, Aomori 036-8564, Japan.
⁹ Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Takara-machi, Kanazawa, Ishikawa 920-8640, Japan.
¹⁰ Division of Functional Genomics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
¹¹ Faculty of Biological Science and Technology, Institute of Science and Engineering, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
¹² Advanced Science Research Center, Institute for Gene Research, Kanazawa University, Takara-machi, Kanazawa, Ishikawa 920-8640, Japan.
¹³ Division of Integrated Omics research, Bioscience Core Facility Research Center for Experimental Modeling of Human Disease, Kanazawa University 13-1 Takara-machi, Kanazawa, Ishikawa 920-8640, Japan.
¹⁴ Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁵ Laboratory of Computational Genomics, School of Life Science, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
¹⁶ Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Takara-machi, Kanazawa, Ishikawa 920-8640, Japan.
¹⁷ Cell-Bionomics Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan; Advanced Science Research Center, Institute for Gene Research, Kanazawa University, Takara-machi, Kanazawa, Ishikawa 920-8640, Japan.
¹⁸ Cell-Bionomics Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan; WPI Nano Life Science Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan; Faculty of Biological Science and Technology, Institute of Science and Engineering, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan; Laboratory of molecular cell biology, School of Natural System, Institute of Science and Engineering, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan. Electronic address: [email protected].

PMID: 37924814
DOI: 10.1016/j.chembiol.2023.10.005

Abstract

Master transcription factors such as TP63 establish super-enhancers (SEs) to drive core transcriptional networks in cancer cells, yet the spatiotemporal regulation of SEs within the nucleus remains unknown. The nuclear pore complex (NPC) may tether SEs to the nuclear pore where RNA export rates are maximal. Here, we report that NUP153, a component of the NPC, anchors SEs to the NPC and enhances TP63 expression by maximizing mRNA export. This anchoring is mediated through protein-protein interaction between the intrinsically disordered regions (IDRs) of NUP153 and the coactivator BRD4. Silencing of NUP153 excludes SEs from the nuclear periphery, decreases TP63 expression, impairs cellular growth, and induces epidermal differentiation of squamous cell carcinoma. Overall, this work reveals the critical roles of NUP153 IDRs in the regulation of SE localization, thus providing insights into a new layer of gene regulation at the epigenomic and spatial level.

Keywords: BRD4; gene expression; intrinsically disordered regions; mRNA export; nuclear pore complex; p63; phase separation; squamous cell carcinoma; super-enhancer.

MeSH terms

Bromodomain Containing Proteins
Carcinoma, Squamous Cell* / genetics
Carcinoma, Squamous Cell* / metabolism
Carcinoma, Squamous Cell* / pathology
Cell Cycle Proteins / metabolism
Humans
Nuclear Pore Complex Proteins / genetics
Nuclear Pore Complex Proteins / metabolism
Nuclear Pore* / metabolism
Nuclear Pore* / pathology
Nuclear Proteins / metabolism
Transcription Factors / metabolism

Substances

Transcription Factors
Nuclear Proteins
Nuclear Pore Complex Proteins
NUP153 protein, human
BRD4 protein, human
Bromodomain Containing Proteins
Cell Cycle Proteins