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Non-enzymatic SETD1A activity drives breast cancer cell proliferation via cyclin K

Kanako Hayashi1,2, Takayuki Hoshii3, Meng Ning1

  • 1Department of Molecular Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan.

Breast Cancer Research : BCR
|August 12, 2025
PubMed
Abstract

Insights

SETD1A promotes breast cancer cell replication via its non-enzymatic function with cyclin K. This SETD1A-cyclin K axis presents a potential therapeutic target for breast cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Breast cancer is a leading cause of cancer death in women globally.
  • SETD1A, a histone methyltransferase, is linked to poor breast cancer prognosis.
  • The precise role of SETD1A in breast cancer progression requires further elucidation.

Purpose of the Study:

  • To investigate the molecular mechanisms driving SETD1A dependency in breast cancer.
  • To understand the non-enzymatic functions of SETD1A in breast cancer cells.

Main Methods:

  • Identification of SETD1A-high breast cancer cell lines using TCGA and DepMap databases.
  • CRISPR knockout of SETD1A in KPL-1 cells.
  • RNA-seq, ChIP-seq, CRISPR-tiling screening, and rescue experiments.

Main Results:

  • SETD1A is highly expressed in ER+/HER2- breast cancer, correlating with shorter survival.
  • SETD1A is essential for cell cycle progression (G1 to S phase) independent of its catalytic domain.
  • SETD1A disruption impairs DNA repair gene expression (RPA3, PRIM1) and transcriptional elongation.
  • The non-catalytic function involves the cyclin K-associated FLOS domain.
  • CR8, a cyclin K degrader, mimicked SETD1A knockout phenotypes in ER+/HER2- and triple-negative breast cancer (TNBC) cells.

Conclusions:

  • SETD1A promotes breast cancer cell replication through its non-enzymatic interaction with cyclin K.
  • The SETD1A-cyclin K axis represents a promising therapeutic target for breast cancer, including TNBC.
Keywords:
Breast cancerEpigenomeH3K4 methyltransferaseSETD1ATranscription

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