Ubiquitination by HUWE1 in tumorigenesis and beyond

Abstract

Ubiquitination modulates a large repertoire of cellular functions and thus, dysregulation of the ubiquitin system results in multiple human diseases, including cancer. Ubiquitination requires an E3 ligase, which is responsible for substrate recognition and conferring specificity to ubiquitination. HUWE1 is a multifaceted HECT domain-containing ubiquitin E3 ligase, which catalyzes both mono-ubiquitination and K6-, K48- and K63-linked poly-ubiquitination of its substrates. Many of the substrates of HUWE1 play a crucial role in maintaining the homeostasis of cellular development. Not surprisingly, dysregulation of HUWE1 is associated with tumorigenesis and metastasis. HUWE1 is frequently overexpressed in solid tumors, but can be downregulated in brain tumors, suggesting that HUWE1 may possess differing cell-specific functions depending on the downstream targets of HUWE1. This review introduces some important discoveries of the HUWE1 substrates, including those controlling proliferation and differentiation, apoptosis, DNA repair, and responses to stress. In addition, we review the signaling pathways HUWE1 participates in and obstacles to the identification of HUWE1 substrates. We also discuss up-to-date potential therapeutic designs using small molecules or ubiquitin variants (UbV) against the HUWE1 activity. These molecular advances provide a translational platform for future bench-to-bed studies. HUWE1 is a critical ubiquitination modulator during the tumor progression and may serve as a possible therapeutic target for cancer treatment.

Coessential Genetic Networks Reveal the Organization and Constituents of a Dynamic Cellular Stress Response

“…We demonstrate that context, in tumor subtype and cell lineage, is associated with dynamic changes in the organization and utilization of stress response modules in a manner reflecting therapeutically-targetable biology. Finally, we identify novel genes in a global stress network, validating that the previously unannotated HAPSTR (C16orf72) promotes cellular adaptation to diverse stressors as a stress-inducible regulator of HUWE1, an E3 ligase which modulates genotoxic, proteotoxic, and hypoxic stress responses (Kao et al, 2018). More broadly, we demonstrate the power of our approach using the global stress response network as proof of principle and provide an interactive web-based tool (http://fireworks.mendillolab.org/) to facilitate studies of other biological networks.…”

Emerging roles of HECT‐type E3 ubiquitin ligases in autophagy regulation

“…Emerging evidence has highlighted that HECT E3s play relevant roles in cancer development and progression by regulating the degradation or the activity of both oncogenes and tumor suppressors. As a consequence, abnormal expression, dysfunction, and mutations of the HECT enzymes have been associated with cancer development and chemoresistance (Kao et al, 2018;Koganti et al, 2018;Lee et al, 2019;Melino et al, 2008;Sanarico et al, 2018).…”

“…The role of HUWE1 in tumorigenesis has been very debated. Both tumor suppressive and oncogenic functions have been reported (Kao et al, 2018). It has been proposed that the dual role of HUWE1 in cancer is influenced by different protein adaptors or post-translational modifications.…”

HUWE1 promotes EGFR ubiquitination and degradation to protect against renal tubulointerstitial fibrosis

“…HUWE1 is a 482‐kD E3 ubiquitin ligase containing a HECT domain. This huge protein is predicted to have powerful functions, including diverse cellular responses that drive cell proliferation and survival . The identified substrates of HUWE1 are p53 and MYC, among others .…”

“…This huge protein is predicted to have powerful functions, including diverse cellular responses that drive cell proliferation and survival. 21,22 The identified substrates of HUWE1 are p53 and MYC, among others. 23,24 Not surprisingly, HUWE1 has been ascribed both putative oncoprotein and tumor suppressor functions.…”