The transcription factor FOXM1 forms functional condensates, the formation of which can be targeted with a specific peptide to suppress breast cancer growth and metastasis.

Identifying phase-separated structures remains challenging, and effective intervention methods are currently lacking1. Here we screened for phase-separated proteins in breast tumour cells and identified forkhead (FKH) box protein M1 (FOXM1) as the most prominent candidate. Oncogenic FOXM1 underwent liquid–liquid phase separation (LLPS) with FKH consensus DNA element, and compartmentalized the transcription apparatus in the nucleus, thereby sustaining chromatin accessibility and super-enhancer landscapes crucial for tumour metastatic outgrowth. Screening an epigenetics compound library identified AMPK agonists as suppressors of FOXM1 condensation. AMPK phosphorylated FOXM1 in the intrinsically disordered region (IDR), perturbing condensates, reducing oncogenic transcription, accumulating double-stranded DNA to stimulate innate immune responses, and endowing discrete FOXM1 with the ability to activate immunogenicity-related gene expressions. By developing a genetic code-expansion orthogo

Identifying phase-separated structures remains challenging, and effective intervention methods are currently lacking1. Here we screened for phase-separated proteins in breast tumour cells and identified forkhead (FKH) box protein M1 (FOXM1) as the most prominent candidate. Oncogenic FOXM1 underwent liquid–liquid phase separation (LLPS) with FKH consensus DNA element, and compartmentalized the transcription apparatus in the nucleus, thereby sustaining chromatin accessibility and super-enhancer landscapes crucial for tumour metastatic outgrowth. Screening an epigenetics compound library identified AMPK agonists as suppressors of FOXM1 condensation. AMPK phosphorylated FOXM1 in the intrinsically disordered region (IDR), perturbing condensates, reducing oncogenic transcription, accumulating double-stranded DNA to stimulate innate immune responses, and endowing discrete FOXM1 with the ability to activate immunogenicity-related gene expressions. By developing a genetic code-expansion orthogo

The transcription factor FOXM1 forms functional condensates, the formation of which can be targeted with a specific peptide to suppress breast cancer growth and metastasis.

The MuvB family of protein complexes regulate cell cycle-dependent transcription, and MuvB in complex with the transcription factors B-MYB and FOXM1 activate mitotic genes during G2. Here the authors ...

Cedars-Sinai Health Sciences University investigators have identified molecular mechanisms that drive inflammation in alcohol-associated liver disease.

Relapsed and refractory multiple myeloma remains a major clinical challenge. This study shows that FOXM1 contributes to resistance against BH3 mimetics in multiple myeloma cells. The FOXM1 inhibitor NB73 enhances the effectiveness of BH3 mimetics by reducing FOXM1 expression and suppressing the MYC pathway. These findings support the development of FOXM1-targeted combinatorial therapies for treating multiple myeloma. Abstract Relapsed and refractory multiple myeloma (RRMM) remains the leading cause of MM mortality. FOXM1 is strongly associated with RRMM, making it a compelling therapeutic target. Through three low-throughput screenings, we have identified nine FDA-approved drugs, including the BH3 mimetic Venetoclax, that synergize with FOXM1 inhibitor NB73 in killing MM cells. Venetoclax has shown effects in 6% of non-t(11;14) and 27% of t(11;14) MM cases. The NB73-Venetoclax combination barely induces acute toxicity in vivo and represses MM cells in vivo and ex vivo. NB73 enhances the ubiquitination and proteasomal degradation of FOXM1, an effect further amplified by Venetoclax. The NB73-Venetoclax combination abolishes FOXM1's binding to promoters of key MYC pathway genes, such as PLK1, leading to significant downregulation of their expression. Furthermore, the PLK1-specific inhibitor GSK461364 synergizes with NB73 to inhibit MM cell growth. Interestingly, NB73 does not sensitize U266 cells, a Venetoclax-resistant t(11;14) MM cell line expressing high FOXM1, to Venetoclax treatment, which is corrected by a new-generation BH3 mimetic Sonrotoclax and ALK inhibitor Ceritinib. Collectively, targeting FOXM1 demonstrates significant potential for enhancing the efficacy of FDA-approved drugs in RRMM. These findings shed new light on the discouraging outcomes of the Phase-III CANOVA study centering Venetoclax with an encouraging molecular clue.

Read the full paper: FOXM1-specific TCR-engineered T cells target non-small cell lung cancer

The transcription factor FOXM1 forms functional condensates, the formation of which can be targeted with a specific peptide to suppress breast cancer growth and metastasis.

The transcription factor FOXM1 forms functional condensates, the formation of which can be targeted with a specific peptide to suppress breast cancer growth and metastasis.

Read the full paper: JAK/STAT1-interferon-ISGylation networks in breast cancer resistance to inhibitors of FOXM1 and CDK4/6