14-3-3σ-NEDD4L axis promotes ubiquitination and degradation of HIF-1α in colorectal cancer

Sicheng Liu; Rui Guo; Hui Xu; Jinneng Yang; Haidan Luo; Sai-Ching Jim Yeung; Kai Li; Mong-Hong Lee; Runxiang Yang

doi:10.1016/j.celrep.2023.112870

14-3-3σ-NEDD4L axis promotes ubiquitination and degradation of HIF-1α in colorectal cancer

Cell Rep. 2023 Aug 29;42(8):112870. doi: 10.1016/j.celrep.2023.112870. Epub 2023 Jul 28.

Authors

Sicheng Liu¹, Rui Guo², Hui Xu³, Jinneng Yang³, Haidan Luo³, Sai-Ching Jim Yeung⁴, Kai Li⁵, Mong-Hong Lee⁶, Runxiang Yang⁷

Affiliations

¹ Department of the Second Medical Oncology, The Third Affiliated Hospital of Kunming Medical University, Kunming 650100, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
² Department of the Second Medical Oncology, The Third Affiliated Hospital of Kunming Medical University, Kunming 650100, China.
³ Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
⁴ Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵ Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China. Electronic address: likai39@mail.sysu.edu.cn.
⁶ Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China. Electronic address: limh33@mail.sysu.edu.cn.
⁷ Department of the Second Medical Oncology, The Third Affiliated Hospital of Kunming Medical University, Kunming 650100, China. Electronic address: 13888876721@163.com.

PMID: 37494179
DOI: 10.1016/j.celrep.2023.112870

Abstract

A hypoxic microenvironment contributes to tumor progression, with hypoxia-inducible factor-1α (HIF-1α) being a critical regulator. We have reported that 14-3-3σ is negatively associated with HIF-1α expression; however, its role in hypoxia-induced tumor progression remains poorly characterized. Here we show that 14-3-3σ suppresses cancer hypoxia-induced metastasis and angiogenesis in colorectal cancer (CRC). 14-3-3σ opposes HIF-1α expression by regulating the protein stability of HIF-1α, thereby decreasing HIF-1α transcriptional activity and suppressing tumor progression. Mechanistic studies show that the 14-3-3σ-interacting protein neural precursor cell-expressed developmentally down-regulated 4-like (NEDD4L) is an E3 ligase that targets HIF-1α. 14-3-3σ promotes the binding of S448-phosphorylated NEDD4L to HIF-1α, thereby enhancing HIF-1α poly-ubiquitination and subsequent proteasome-mediated degradation. Consistent with this anti-tumorigenic function for 14-3-3σ, low 14-3-3σ expression levels correlate with poor CRC patient survival, and 14-3-3σ enhances the response of CRC to bevacizumab. These results reveal an important mechanism for 14-3-3σ in tumor suppression through HIF-1α regulation.

Keywords: 14-3-3σ; CP: Cancer; HIF-1α; NEDD4L; bevacizumab; colorectal cancer; ubiquitination.