Cancer-associated missense mutations enhance the pluripotency reprogramming activity of OCT4 and SOX17

TY - JOUR

T1 - Cancer-associated missense mutations enhance the pluripotency reprogramming activity of OCT4 and SOX17

AU - Srivastava, Yogesh

AU - Tan, Daisylyn Senna

AU - Malik, Vikas

AU - Weng, Mingxi

AU - Javed, Asif

AU - Cojocaru, Vlad

AU - Wu, Guangming

AU - Veerapandian, Veeramohan

AU - Cheung, Lydia W T

AU - Jauch, Ralf

N1 - © 2019 Federation of European Biochemical Societies.

PY - 2020/1

Y1 - 2020/1

N2 - The functional consequences of cancer-associated missense mutations are unclear for the majority of proteins. We have previously demonstrated that the activity of SOX and Pit-Oct-Unc (POU) family factors during pluripotency reprogramming can be switched and enhanced with rationally placed point mutations. Here, we interrogated cancer mutation databases and identified recurrently mutated positions at critical structural interfaces of the DNA-binding domains of paralogous SOX and POU family transcription factors. Using the conversion of mouse embryonic fibroblasts to induced pluripotent stem cells as functional readout, we identified several gain-of-function mutations that enhance pluripotency reprogramming by SOX2 and OCT4. Wild-type SOX17 cannot support reprogramming but the recurrent missense mutation SOX17-V118M is capable of inducing pluripotency. Furthermore, SOX17-V118M promotes oncogenic transformation, enhances thermostability and elevates cellular protein levels of SOX17. We conclude that the mutational profile of SOX and POU family factors in cancer can guide the design of high-performance reprogramming factors. Furthermore, we propose cellular reprogramming as a suitable assay to study the functional impact of cancer-associated mutations.

AB - The functional consequences of cancer-associated missense mutations are unclear for the majority of proteins. We have previously demonstrated that the activity of SOX and Pit-Oct-Unc (POU) family factors during pluripotency reprogramming can be switched and enhanced with rationally placed point mutations. Here, we interrogated cancer mutation databases and identified recurrently mutated positions at critical structural interfaces of the DNA-binding domains of paralogous SOX and POU family transcription factors. Using the conversion of mouse embryonic fibroblasts to induced pluripotent stem cells as functional readout, we identified several gain-of-function mutations that enhance pluripotency reprogramming by SOX2 and OCT4. Wild-type SOX17 cannot support reprogramming but the recurrent missense mutation SOX17-V118M is capable of inducing pluripotency. Furthermore, SOX17-V118M promotes oncogenic transformation, enhances thermostability and elevates cellular protein levels of SOX17. We conclude that the mutational profile of SOX and POU family factors in cancer can guide the design of high-performance reprogramming factors. Furthermore, we propose cellular reprogramming as a suitable assay to study the functional impact of cancer-associated mutations.

KW - Animals

KW - Cell Differentiation

KW - Cells, Cultured

KW - Cellular Reprogramming

KW - Embryonic Stem Cells/cytology

KW - Gene Expression Profiling

KW - Humans

KW - Induced Pluripotent Stem Cells/cytology

KW - Mice

KW - Mutation, Missense

KW - Neoplasms/genetics

KW - Octamer Transcription Factor-3/genetics

KW - SOXB1 Transcription Factors/genetics

KW - SOXF Transcription Factors/genetics

U2 - 10.1111/febs.15076

DO - 10.1111/febs.15076

M3 - Article

C2 - 31569299

SN - 1742-464X

VL - 287

SP - 122

EP - 144

JO - FEBS Journal

JF - FEBS Journal

IS - 1

ER -