The E3 ubiquitin ligase WWP1 sustains the growth of acute myeloid leukaemia

Abstract

The E3 ubiquitin ligase (E3) WWP1 is an oncogenic factor implicated in the maintenance of different types of epithelial cancers. The role of WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) in haematological neoplasms remains unknown. Acute myeloid leukaemia (AML) is characterized by the expansion of malignant myeloid cells blocked at different stages of differentiation. Here we report that the expression of WWP1 is significantly augmented in a large cohort of primary AML patients and in AML cell lines, compared with haematopoietic cells from healthy donors. We show that WWP1 inactivation severely impairs the growth of primary AML blasts and cell lines in vitro. In vivo, we observed a reduced leukaemogenic potential of WWP1-depleted AML cells upon transplantation into immunocompromised mice. Mechanistically, WWP1 inactivation induces the accumulation of its protein substrate p27Kip1, which ultimately contributes to G0/G1 cell cycle arrest of AML blasts. In addition, WWP1 depletion triggers the autophagy signalling and reduces survival of leukaemic cells. Collectively, our findings provide molecular insights into the anti-cancer potential of WWP1 inhibition, suggesting that this E3 is a promising biomarker and druggable target in AML.

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

“…Silencing WWP1 expression in AML blasts activates autophagy which, in turn, decreases viability and induces differentiation of leukemic cells (Sanarico et al ., ). WWP1 overexpression in AML patients indeed causes stabilization of oncoproteins such as PML‐RARα and FLT3/ITD, whose turnover is regulated in an autophagy‐dependent manner.…”

“…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).…”

“…Modification of UVRAG by SMURF1 was found to be functionally relevant for autophagy-dependent degradation of the epidermal growth factor receptor and, as a result, for inhibiting hepatocellular carcinoma cell proliferation and tumor growth (Feng et al, 2019). Silencing WWP1 expression in AML blasts activates autophagy which, in turn, decreases viability and induces differentiation of leukemic cells (Sanarico et al, 2018). WWP1 overexpression in AML patients indeed causes stabilization of oncoproteins such as PML-RARa and FLT3/ITD, whose turnover is regulated in an autophagy-dependent manner.…”

“…WW domain-containing E3 ubiquitin protein ligase 1 is a well-established oncogene that has been implicated in the development of several human cancers (Chen et al, 2007;Lee et al, 2019;Sanarico et al, 2018). Unlike the other members of the HECT family, WWP1 functions as a negative regulator of the autophagic pathway (Sanarico et al, 2018). WWP1 knockdown in acute myeloid leukemia (AML) cells indeed leads to autophagy induction, which is accompanied by increased total levels of LC3 and ATG7 and accumulation of lipidated LC3.…”

Functional role of WW domain‐containing proteins in tumor biology and diseases: Insight into the role in ubiquitin‐proteasome system

“…Selective inhibition of WW domain‐containing E3 ligase has been a novel strategy in the field of cancer therapy. For example, WWP1 has been found amplified in numerous tumors, while downregulation of WWP1 attenuates leukemic cell growth . Similar to WWP1, a small‐molecule inhibitor of WWP2 has been investigated and might have an anti‐tumor function .…”