title: Role of SUMO activating enzyme in cancer stem cell maintenance and self-renewal.
abstract: Cancer stem cells (CSCs) have key roles in treatment resistance, tumour metastasis and relapse. Using colorectal cancer (CC) cell lines, patient-derived xenograft (PDX) tissues and patient tissues, here we report that CC CSCs, which resist chemoradiation, have higher SUMO activating enzyme (E1) and global SUMOylation levels than non-CSCs. Knockdown of SUMO E1 or SUMO conjugating enzyme (E2) inhibits CC CSC maintenance and self-renewal, while overexpression of SUMO E1 or E2 increases CC cell stemness. We found that SUMOylation regulates CSCs through Oct-1, a transcription factor for aldehyde dehydrogenases (ALDHs). ALDH activity is not only a marker for CSCs but also important in CSC biology. SUMO does not modify Oct-1 directly, but regulates the expression of TRIM21 that enhances Oct-1 ubiquitination and, consequently, reducing Oct-1 stability. In summary, our findings suggest that SUMOylation could be a target to inhibit CSCs and ultimately to reduce treatment resistance, tumour metastasis and relapse.
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Du
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
authors.forename: Yi-Jia
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, City of Hope National Medical Center, Duarte, California 91010, USA.
authors.forename: Marwan
authors.initials: M
authors.lastname: Fakih
authors.affiliation: Department of Surgery, City of Hope National Medical Center, Duarte, California 91010, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Wiatrek
authors.affiliation: Department of Surgery, City of Hope National Medical Center, Duarte, California 91010, USA.
authors.forename: Marjun
authors.initials: M
authors.lastname: Duldulao
authors.affiliation: Department of Surgery, City of Hope National Medical Center, Duarte, California 91010, USA.
authors.forename: Zhenbin
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pathology, City of Hope National Medical Center, Duarte, California 91010, USA.
authors.forename: Peiguo
authors.initials: P
authors.lastname: Chu
authors.affiliation: Department of Surgery, City of Hope National Medical Center, Duarte, California 91010, USA.
authors.forename: Julio
authors.initials: J
authors.lastname: Garcia-Aguilar
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D002277:Carcinoma / Q000201:enzymology*; D000066673:Cell Self Renewal; D015179:Colorectal Neoplasms / Q000201:enzymology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000201:enzymology*; D050811:Octamer Transcription Factor-1 / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D058207:Sumoylation; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000099207:SS-A Antigen
chemical_list: D000444:Aldehyde Dehydrogenase; D050811:Octamer Transcription Factor-1; D012261:Ribonucleoproteins; D025841:Small Ubiquitin-Related Modifier Proteins; D044767:Ubiquitin-Protein Ligases; D000099207:SS-A Antigen