Chasing for E3 Ubiquitin Ligase Smurf2 in Cancer and Beyond

Introduction

The lack of an effective treatment together with the high mortality rates of cancer patients emphasize the urgent need to explore into novel therapeutic targets and paradigms, which can subsequently be incorporated in cancer treatment.

Recently, we discovered Smurf2 – an E3 ubiquitin ligase, chromatin modifier and signal transduction regulator, as a key cellular factor operating in cells to prevent cell transformation and carcinogenesis. Our studies also uncovered that Smurf2 operates as an important regulator of DNA damage response (DDR), gene expression, and genomic integrity maintenance spanning through and interlocking these components (Blank M et al., Nature Med 2012; Zou et al., BBA-Rev Cancer 2015). These intriguing findings prompted us to further investigate and characterize molecular processes operating under Smurf2 jurisdictions in mammalian normal and tumor cells and tissues.

Materials and Methods

A spectrum of experimental approaches ranging from genetics and biochemistry through molecular biology to animal pathophysiology and human sample analyses were employed.

Results and discussion

We identified a novel mechanism by which Smurf2 regulates genome integrity – through stability regulation of DNA topoisomerase IIα (Topo IIα). Topo IIα is a key cellular enzyme implicated in chromatin organization, dynamics and unaltered chromosome inheritance, and the target of a few major chemotherapeutic drugs used in clinics. In particular, we found that Smurf2 directly binds and modifies the ubiquitination code of Topo IIα, thereby protecting this enzyme from degradation, and preventing the formation of pathological DNA bridges (Emanuelli et al., Cancer Res 2017). These bridges are considered as one of the major causes of chromosomal translocations, and are often an output of the compromised decatenation checkpoint regulated by Topo IIα.

Our second line of investigation led to elucidation of Smurf2 as a bona fide negative regulator of A-type nuclear lamins, in particular of lamin A and its disease-associated form progerin, whose expression underlies the development of a devastating premature aging syndrome–HGPS (Borroni et al., Aging Cell 2018). Essentially, in addition to HGPS, progerin accumulation has been associated with a physiological aging, and cancer. This association suggests that the targeting of A-lamins in cancer might be a promising direction to eradicate tumor cells.

Conclusion

Our findings establish Smurf2 as a key cellular factor involved in the regulation of pivotal cellular processes in mammalian cells. Further in depth analyses of biological functions of Smurf2, and its targeted regulation by pharmacological intervention, might represent a feasible approach for personalized therapy of cancer.