Kanazawa University successfully controls cancer cell growth by manipulating super-enhancers — Expectation for treatment development and drug discovery

The research group led by Associate Professor Masaharu Hazawa, Postdoctoral Researcher Dini Kurnia Ikliptikawati, Graduate Student Yuki Iwashima (at the time of research), and Professor Richard Wong of the Institute for Frontier Science Initiative and the Nano-Life Science Institute at Kanazawa University announced they have discovered that cancer cell proliferation can be suppressed by controlling the super-enhancers (SEs) that activate oncogenes essential for malignant cancer progression. The results will lead to the development of new cancer treatments and were published in the journal Cell Chemical Biology on November 3.

Within cells, biopolymers such as proteins and RNA assemble in specific regions to regulate various biological processes, such as gene expression and information signal transmission. Although the conversion of DNA information into mRNA information (transcription) occurs in the nucleus, the final stage of conversion of the mRNA information into a functional protein molecule takes place in the cytoplasm. Many genes involved in cancer cell proliferation and metastasis are known to be overexpressed, but the details of the mechanisms behind their efficient expression and maintenance were unclear.

Through molecular imaging analysis of the SEs that induce transcription, the research group revealed that some of them exist around the nuclear envelope. Furthermore, the SEs present near the nuclear membrane were involved in the maintenance and expression of the oncogene TP63, which controls the proliferation and metastasis of squamous cell carcinoma cells.

When the research group analyzed the mechanism through which the spatial arrangement of the SEs is controlled, they found that the protein nucleoporin 153 (NUP153) holds them near the nuclear pore. NUP153 is a component of the nuclear pore complex, a molecular transport system that is scattered throughout the nuclear membrane.

In cancer cells in which NUP153 expression has been suppressed, SEs cannot be localized near the nuclear envelope, resulting in the nuclear export of TP63 mRNA being significantly reduced. This leads to decreased TP63 protein expression and cell growth being arrested.

This study revealed that the control of the spatiotemporal arrangement of SEs within the nucleus by the nuclear pore complex in the nuclear membrane is an important molecular basis for ensuring cancer gene maintenance and expression. The above conclusions should lead to the development of new drugs and cancer treatments that target the spatial layout of the SEs.

Hazawa commented, "Current research has revealed the importance of the intranuclear spatial arrangement of the super-enhancers that induce gene expression. Our future goal is to clarify the mechanism that determines the spatial arrangement of the super-enhancers in the nuclear structural dynamics of repeated collapse and reconstruction."