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

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

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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.

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Humans Nuclear Pore Transcription Factors Nuclear Proteins Nuclear Pore Complex Proteins Carcinoma, Squamous Cell Bromodomain Containing Proteins Cell Cycle Proteins BRD4 gene expression intrinsically disordered regions mRNA export nuclear pore complex p63 phase separation squamous cell carcinoma super-enhancer Journal Article Research Support, Non-U.S. Gov't

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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. 2023-11-03. Super-enhancer trapping by the nuclear pore via intrinsically disordered regions of proteins in squamous cell carcinoma cells.. https://doi.org/10.1016/j.chembiol.2023.10.005

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