SUMO1 degrader induces ER stress and ROS accumulation through deSUMOylation of TCF4 and inhibition of its transcription of StarD7 in colon cancer

• Published in: Molecular carcinogenesis Vol. 62; no. 9; pp. 1249 - 1262
• Main Authors: Zhao, Yin Quan, Jin, Hong Ri, Kim, Daeho, Jung, Sung Han, Liu, Sheng, Wan, Jun, Lo, Ho‐Yin, Fu, Xue Qi, Wang, Quan, Hao, Chunhai, Bellail, Anita C.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.09.2023
• Subjects: Antitumor activity; Carrier Proteins - genetics; Cell growth; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; Colorectal cancer; CRISPR; Degradation; Endoplasmic reticulum; Endoplasmic Reticulum Stress; ER stress; Genomes; Humans; Lymphocytes T; Organoids; Reactive oxygen species; Reactive Oxygen Species - metabolism; RNA, Messenger; StarD7; SUMO protein; SUMO-1 Protein - genetics; SUMO-1 Protein - metabolism; SUMO1 degrader; TCF4; Transcription; Transcription Factor 4 - metabolism; Ubiquitin; Xenografts; ER stress; TCF4; SUMO1 degrader; colon cancer; StarD7
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.23560

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).