The histone methyltransferase SETDB1 catalyzes the addition of methyl groups to histone H3 at lysine 9, and upregulation of SETDB1 is associated with poor prognosis in cancer patients. Here, we describe how overexpression of SETDB1 contributes to colorectal cancer (CRC) tumorigenesis and drug resistance. We show that SETDB1 is upregulated in CRC, and its level correlates with poor clinical outcome. SETDB1 attenuation inhibits CRC cell proliferation Mechanistically, SETDB1 promotes cell proliferation by upregulating Akt activation. Further, SETDB1 is essential for the tumorigenic activity of Akt. Functional characterization revealed that inhibition of SETDB1 reduces cell growth in CRC resistant to targeted treatments in vitro and in vivo, KRAS-mutated CRC included. Taken together, our results indicate that SETDB1 is a major driver of CRC and may serve as a potential target for the treatment of KRAS-mutated CRC.

组蛋白甲基转移酶SETDB1催化在赖氨酸9处向组蛋白H3添加甲基，SETDB1的上调与癌症患者的不良预后有关。在这里，我们描述了SETDB1的过表达如何促进结直肠癌（CRC）的肿瘤发生和耐药性。我们显示SETDB1在CRC中被上调，其水平与不良的临床预后相关。SETDB1衰减从机械上抑制CRC细胞增殖，SETDB1通过上调Akt激活来促进细胞增殖。此外，SETDB1对于Akt的致癌活性至关重要。功能表征表明，SETDB1的抑制减少了CRC至靶向治疗耐药的细胞生长的体外和体内，包括KRAS突变的CRC。综上所述，我们的结果表明SETDB1是CRC的主要驱动力，并可能成为治疗KRAS突变CRC的潜在靶标。