The multifunctional role of SPANX-A/D protein subfamily in the promotion of pro-tumoural processes in human melanoma

Itziar Urizar-Arenaza,Nerea Osinalde,Maria Dolores Boyano,Jose Antonio Rodriguez,Vyacheslav Akimov,Nerea Subiran,Arantza Perez-Valle,Irina Kratchmarova,Blagoy Blagoev,Aintzane Asumendi,Iraia Muñoa-Hoyos,Aitor Benedicto

doi:10.1038/s41598-021-83169-1

Abstract

Human sperm protein associated with the nucleus on the X chromosome (SPANX) genes encode a protein family (SPANX-A, -B, -C and -D), whose expression is limited to the testis and spermatozoa in normal tissues and various tumour cells. SPANX-A/D proteins have been detected in metastatic melanoma cells, but their contribution to cancer development and the underlying molecular mechanisms of skin tumourigenesis remain unknown. Combining functional and proteomic approaches, the present work describes the presence of SPANX-A/D in primary and metastatic human melanoma cells and how it promotes pro-tumoural processes such as cell proliferation, motility and migration. We provide insights into the molecular features of skin tumourigenesis, describing for the first time a multifunctional role of the SPANX-A/D protein family in nuclear function, energy metabolism and cell survival, considered key hallmarks of cancer. A better comprehension of the SPANX-A/D protein subfamily and its molecular mechanisms will help to describe new aspects of tumour cell biology and develop new therapeutic targets and tumour-directed pharmacological drugs for skin tumours.

Highlights

Human sperm protein associated with the nucleus on the X chromosome (SPANX) genes encode a protein family (SPANX-A, -B, -C and -D), whose expression is limited to the testis and spermatozoa in normal tissues and various tumour cells
Among the 246 putative SPANX-A interactors, we found several proteins involved in the following processes: cell metabolism, such as pyruvate kinase (PKM), D-3-phosphoglycerate dehydrogenase (PHGDH) or pyruvate dehydrogenase E1 component subunit alpha (PDHA1); specific enzymes that participate in glucose catabolism; cell structure proteins related to the cytoskeleton, such as actin (ACTG1), α/β tubulins (TUBA1B and TUBB4B) or keratins (KRT1, KRT2 AND KRT9); and cell survival, such as mitogen-activated protein kinase 1 (MAPK1), inosine-5-monophosphate dehydrogenase 2 (IMPDH2) or F-box only protein 50 (NCCRP1)
Through a combination of functional and proteomic approaches, we proved that SPANX-A/D proteins play a multifunctional role in skin tumourigenesis, providing insight into how this protein family may promote pro-tumoural processes in human primary melanoma cells (Fig. 4)

Summary

Introduction

Human sperm protein associated with the nucleus on the X chromosome (SPANX) genes encode a protein family (SPANX-A, -B, -C and -D), whose expression is limited to the testis and spermatozoa in normal tissues and various tumour cells. SPANX-A/D proteins have been detected in metastatic melanoma cells, but their contribution to cancer development and the underlying molecular mechanisms of skin tumourigenesis remain unknown. We discovered that SPANX-A/D proteins are involved in numerous functions, including nuclear envelope organisation, sperm movement and m etabolism[7], suggesting their potential as promising targets for sperm fertility management In addition to their physiological function in sperm fertility, SPANX, similar to other CTAs, plays a pathological role because it is expressed in various tumours originating from nongametic cells[3,6]. The molecular mechanisms driving the malignant differentiation of tumour cells remain unknown

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