puc-header

LSD1 Destabilizes FBXW7 Independent of Its Demethylase Activity

49 Pages Posted: 9 Nov 2018 Publication Status: Under Review

See all articles by Huiyin Lan

Huiyin Lan

Zhejiang University - Institute of Translational Medicine

Mingjia Tan

University of Michigan at Ann Arbor - Division of Radiation and Cancer Biology

Qiang Zhang

University of Michigan at Ann Arbor - Division of Radiation and Cancer Biology

Fei Yang

Zhejiang University - Institute of Translational Medicine

Hua Li

University of Michigan at Ann Arbor - Division of Radiation and Cancer Biology

Xiufang Xiong

Zhejiang University - Institute of Translational Medicine

Yi Sun

Zhejiang University - Institute of Translational Medicine; University of Michigan at Ann Arbor - Division of Radiation and Cancer Biology

More...

Abstract

FBXW7 acts as a typical tumor suppressor, with loss of function alterations in human cancers, by promoting ubiquitylation and degradation of many oncoproteins. Lysine-specific demethylase 1 (LSD1) is a well-characterized histone demethylase. Whether LSD1 has demethylase-independent activity remains elusive. Here we report that LSD1 directly binds to FBXW7 to destabilize FBXW7 independent of its demethylase activity. Specifically, LSD1 is a pseudo-substrate of FBXW7 and LSD1-FBXW7 binding does not trigger LSD1 ubiquitylation, instead promote FBXW7 self-ubiquitylation by preventing FBXW7 dimerization. The self-ubiquitylated FBXW7 is subjected to degradation by proteasome and lysosome in a manner dependent of autophagy protein p62/SQSTM1. Biologically, LSD1 destabilizes FBXW7 to abrogate its functions in growth suppression, NHEJ repair and radioprotection. Collectively, our study revealed a previously unknown activity of LSD1, which likely contributes to its oncogenic function. Targeting LSD1 protein, rather than its demethylase activity, might be a unique approach for LSD1-based drug discovery for anti-cancer application.

Keywords: Degradation, DNA damage repair, Protein demethylation, Radiation sensitization, SCF E3 ligase, Ubiquitylation

Suggested Citation

Lan, Huiyin and Tan, Mingjia and Zhang, Qiang and Yang, Fei and Li, Hua and Xiong, Xiufang and Sun, Yi, LSD1 Destabilizes FBXW7 Independent of Its Demethylase Activity (November 9, 2018). Available at SSRN: https://ssrn.com/abstract=3281653 or http://dx.doi.org/10.2139/ssrn.3281653
This version of the paper has not been formally peer reviewed.

Huiyin Lan

Zhejiang University - Institute of Translational Medicine

China

Mingjia Tan

University of Michigan at Ann Arbor - Division of Radiation and Cancer Biology

1500 E Medical Center Dr.
UH B2C490
Ann Arbor, 48109-5010
United States

Qiang Zhang

University of Michigan at Ann Arbor - Division of Radiation and Cancer Biology

1500 E Medical Center Dr.
UH B2C490
Ann Arbor, 48109-5010
United States

Fei Yang

Zhejiang University - Institute of Translational Medicine

China

Hua Li

University of Michigan at Ann Arbor - Division of Radiation and Cancer Biology

1500 E Medical Center Dr.
UH B2C490
Ann Arbor, 48109-5010
United States

Xiufang Xiong

Zhejiang University - Institute of Translational Medicine

China

Yi Sun (Contact Author)

Zhejiang University - Institute of Translational Medicine ( email )

China

University of Michigan at Ann Arbor - Division of Radiation and Cancer Biology ( email )

1500 E Medical Center Dr.
UH B2C490
Ann Arbor, 48109-5010
United States

Click here to go to Cell.com

Paper statistics

Abstract Views
559
Downloads
14
PlumX Metrics