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시티오브호프, SUMO화 저해제로 발암 억제 가능성 - 바이오스펙테이터

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시티오브호프, SUMO화 저해제로 발암 억제 가능성

입력 2019-01-04 08:23 수정 2019-01-04 08:23

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위안 첸 교수팀, 대장암 이종이식 모델에서 효능 확인...SUMO E1 저해제로 단백질 '수모화'(SUMOylation)의 조절장애를 막아 c-Myc에 의한 암 발병 저해

시티오브호프(City of Hope) 연구소 분자의학부 위안 첸(Yuan Chen) 교수 연구팀이 개발한 SUMO E1[small ubiquitin-like modifier (SUMO)-activating enzyme (E1), SAE] 저해제 ‘COH000’를 적용해 MYC(c-Myc) 유전자로 발병하는 암 중 대장암 이종이식 모델에서 효능이 확인됐다. 연구결과는 ‘Cell Chemical Biology’에 지난달 게재됐다.

SUMO는 유비퀴틴에 연관된 작은 단백질로 다양한 타깃 단백질의 리신 잔기에 결합해 기능에 영향을 준다. 단백질이 합성되고 SUMO가 결합하는 과정(SUMOylation)은 진핵세포에서 신호전달, 전사조절, 세포 성장 조절 등 다양한 현상들에 영향을 미칠 수 있다고 밝혀져 있다.

단백질 기능을 조절하는 ‘번역 후 변형’(Post-translational modification, PTM)에 대한 연구가 진행됨에 따라 ‘유비퀴틴’이나 SUMO 같은 ‘유비퀴틴 유사(ubiquitin-like, Ubl) 단백질’에 의해 번역 후 변형과정이 비정상적으로 일어나면 암, 신경퇴행성 질환, 바이러스성 감염 질환이 발병할 수 있다는 연구결과가 발표되고 있다.

번역 후 변형과정 중 SUMOylation의 조절장애는 다양한 암종에서 확인됐다. 이에 Ubl 조절인자를 타깃으로 하는 치료제 연구가 진행되고 있다. SUMO E1을 타깃해 c-Myc이나 KRas로 인한 암 발병을 막을 수 있으며, 암세포의 줄기능(stemness)과 저항성이 낮아진다고 발표됐다.

그러나 현재까지 SUMO E1 같은 Ubl 활성 효소를 저해하는 유일한 방법은 ATP 결합부위를 타깃하는 것이었다. 시티오브호프 연구진은 이번 논문에서 SUMO E1의 다른 저해부위(allosteric inhibitory site)를 찾았다고 밝혔다. 연구진이 개발한 ‘COH000’은 기존 ATP 결합부위가 아닌 Cys30과 결합해 ATP와 경쟁할 필요 없이 다른 저해부위에 붙어 SUMO E1의 활성을 억제하고 분해를 돕는다. 또한 비정상적으로 나타나는 SUMOylation을 억제함으로써 c-Myc의 발현을 억제하는데, 그 과정에서 miR-34b의 발현을 높이는 것이 림프종과 대장암 세포주 및 대장암 이종이식 마우스 모델에서 확인됐다. miR-34b의 발현이 높아지면 c-Myc 수치를 낮추는 것으로 알려져 있다.

비정상적인 c-Myc의 과발현은 이미 다양한 암종에서 확인됐다. 난소암의 50%, 간세포암의 30%는 MYC 유전자의 과발현에 의한 것이다. 씨티오브호프 연구진은 SUMOylation을 조절해 c-Myc 기반 암 발병을 막을 것으로 기대하고 있다.

한편, 위안 첸 교수는 수모 바이오사이언스(SUMO Biosciences)의 공동설립자다.

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