BAP1 has a survival role in cutaneous melanoma

J Invest Dermatol. 2015 Apr;135(4):1089-1097. doi: 10.1038/jid.2014.528. Epub 2014 Dec 18.

Abstract

Although the pattern of BAP1 inactivation in ocular melanoma specimens and in the BAP1 cutaneous melanoma (CM)/ocular melanoma predisposition syndrome suggests a tumor suppressor function, the specific role of this gene in the pathogenesis of CM is not fully understood. We thus set out to characterize BAP1 in CM and discovered an unexpected pro-survival effect of this protein. Tissue and cell lines analysis showed that BAP1 expression was maintained, rather than lost, in primary melanomas compared with nevi and normal skin. Genetic depletion of BAP1 in melanoma cells reduced proliferation and colony-forming capability, induced apoptosis, and inhibited melanoma tumor growth in vivo. On the molecular level, suppression of BAP1 led to a concomitant drop in the protein levels of survivin, a member of anti-apoptotic proteins and a known mediator of melanoma survival. Restoration of survivin in melanoma cells partially rescued the growth-retarding effects of BAP1 loss. In contrast to melanoma cells, stable overexpression of BAP1 into immortalized but non-transformed melanocytes did suppress proliferation and reduce survivin. Taken together, these studies demonstrate that BAP1 may have a growth-sustaining role in melanoma cells, but that its impact on ubiquitination underpins a complex physiology, which is context and cell dependent.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Cell Cycle
  • Cell Proliferation
  • Cell Survival
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor
  • Humans
  • Inhibitor of Apoptosis Proteins / metabolism
  • Melanocytes / cytology
  • Melanoma / metabolism*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • RNA, Messenger / metabolism
  • Skin Neoplasms / metabolism*
  • Survivin
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin Thiolesterase / metabolism*

Substances

  • BAP1 protein, human
  • BAP1 protein, mouse
  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • RNA, Messenger
  • Survivin
  • Tumor Suppressor Proteins
  • Ubiquitin Thiolesterase

Supplementary concepts

  • Melanoma, Cutaneous Malignant