Small molecule degraders of small ubiquitin-related modifier 1 (SUMO1) induce SUMO1 degradation in colon cancer cells and inhibits the cancer cell growth; however, it is unclear how SUMO1 degradation leads to the anticancer activity of the degraders. Genome-wide CRISPR-Cas9 knockout screen has identified StAR-related lipid transfer domain containing 7 (StarD7) as a critical gene for the degrader's anticancer activity. Here, we show that both StarD7 mRNA and protein are overexpressed in human colon cancer and its knockout significantly reduces colon cancer cell growth and xenograft progression. The treatment with the SUMO1 degrader lead compound HB007 reduces StarD7 mRNA and protein levels and increases endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) production in colon cancer cells and three-dimensional (3D) organoids. The study further provides a novel mechanism of the compound anticancer activity that SUMO1 degrader-induced decrease of StarD7 occur through degradation of SUMO1, deSUMOylation and degradation of T cell-specific transcription 4 (TCF4) and thereby inhibition of its transcription of StarD7 in colon cancer cells, 3D organoids and patient-derived xenografts (PDX).
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http://dx.doi.org/10.1002/mc.23560 | DOI Listing |
Ann Oncol
January 2025
Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York, United States. Electronic address:
Background: Prospective data comparing watch-and-wait (WW) to mandatory total mesorectal excision (TME) in patients with locally advanced rectal cancer (LARC) remains limited, as randomized control trials assessing these two treatment approaches are considered impractical. This pooled analysis of the CAO/ARO/AIO-12 and OPRA trials analyzes survival outcomes among LARC patients managed with either a selective WW or mandatory TME strategy following total neoadjuvant therapy (TNT).
Patients And Methods: The CAO/ARO/AIO-12 and OPRA trials were multicenter, phase II trials that randomized patients with stage II/III rectal cancer to receive either induction or consolidation chemotherapy as part of TNT.
Ann Surg Oncol
January 2025
Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway.
Dis Colon Rectum
February 2025
Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Dis Colon Rectum
February 2025
Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Ohio.
Background: Patients with Crohn's disease face an elevated risk of colorectal cancer, in part due to underlying chronic inflammation. Biologic therapy is the mainstay of medical treatment; however, the impact of treatment on colorectal cancer-related outcomes remains unclear.
Objective: To investigate the association between prior exposure to biologic treatment and colorectal cancer-related outcomes in patients with underlying Crohn's disease.
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