Page 30 - F. Cell biology

[F. Cell biology-19]

MYC suppresses tumor necrosis factor-induced necroptosis

by inhibiting the interaction between RIPK1 and RIPK3

Daehyeon Seong¹˙#, Manhyung Jeong¹˙#, Eun-Woo Lee²˙*, Jaewhan Song¹˙*

¹Biochemistry, Yonsei University, Seoul 03722, Republic of Korea, ²Metabolic Regulation Research Center, Korea

Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea

MYC is an oncogene that regulates various cellular processes, including proliferation, differentiation, inflammation,
and metabolism. We observed that MYC functions as a negative regulator of necroptosis. Depletion of MYC using

siRNA, shRNA, and CRISPR/Cas9 knockout systems accelerated necroptosis, which was restored to normal levels by

reconstitution. Interestingly, both MYC-nick and MYC-NLS mutants, which are predominantly expressed in the
cytosol, could restore necroptosis, suggesting that cytosolic MYC is indispensable as an anti-necroptotic factor. We
observed, in detail, that MYC could bind to RIPK3 in the cytosol blocking the interaction between RIPK1 and RIPK3

upon stimulation of necroptosis. To assess whether this process could be applied to cancer therapy, we further
tested the effect of necroptosis on the suppression of tumorigenesis in a leukemia cell line. The growth of the

shMYC-Molm13 cell line skin xenografts was severely suppressed by the stimulation of necroptosis, implying that
necroptosis could suppress cancer cell growth and that its combination with MYC inhibition may lead to a stronger

cancer regression effect.