TY - JOUR
T1 - Multi-omics Profiling Shows BAP1 Loss Is Associated with Upregulated Cell Adhesion Molecules in Uveal Melanoma
AU - Baqai, Usman
AU - Purwin, Timothy J.
AU - Bechtel, Nelisa
AU - Chua, Vivian
AU - Han, Anna
AU - Hartsough, Edward J.
AU - Kuznetsoff, Jeffim N.
AU - Harbour, J. William
AU - Aplin, Andrew E.
N1 - Funding Information:
U. Baqai reports grants from Melanoma Research Foundation Medical Student Award during the conduct of the study. E.J. Hartsough reports grants from NIH/NCI, DoD/CDMRP, W.W. Smith Charitable Trusts, American Cancer Society - IRG, and Sidney Kimmel Cancer Center during the conduct of the study. J.W. Harbour reports grants from Melanoma Research Alliance during the conduct of the study; grants from NCI, other support from Castle Biosciences and Immunoncore outside the submitted work. A.E. Aplin reports grants from NIH outside the submitted work; and A.E. Aplin reports receiving a commercial research grant from Pfizer, Inc. (2013-2017) and has ownership interest in patent number 9880150. No disclosures were reported by the other authors.
Funding Information:
We thank Dr. Claudia Capparelli, Dr. Nicole Wilski, and Signe Caksa for valuable feedback during the preparation of this article. This work was supported by NIH/ NCI grants R01s, CA253977 and CA257505, and P01 CA114046 project 4 to A.E. Aplin. In addition, the work was supported by NIH/NCI R00 CA207855 and the W.W. Smith Charitable Trusts grants to E.J. Hartsough and by the Melanoma Research Foundation Medical Student Award 2020 to U. Baqai. The Sidney Kimmel Cancer Center Flow Cytometry and Translational Pathology Core Facilities are supported by NIH/NCI (P30 CA056036). The RPPA studies were performed at the Functional Proteomics Core Facility at The University of Texas, MD Anderson Cancer Center, which is supported by an NCI Cancer Center Support Grant (P30 CA16672).
Publisher Copyright:
©2022 American Association for Cancer Research.
PY - 2022/8
Y1 - 2022/8
N2 - BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene that is mutated in cancer, including uveal melanoma. Loss-of-function BAP1 mutations are associated with uveal melanoma metastasis and poor prognosis, but the mechanisms underlying these effects remain unclear. Upregulation of cell–cell adhesion proteins is involved with collective migration and metastatic seeding of cancer cells. Here, we show that BAP1 loss in uveal melanoma patient samples is associated with upregulated gene expression of multiple cell adhesion molecules (CAM), including E-cadherin (CDH1), cell adhesion molecule 1 (CADM1), and syndecan-2 (SDC2). Similar findings were observed in uveal melanoma cell lines and single-cell RNA-sequencing data from uveal melanoma patient samples. BAP1 reexpression in uveal melanoma cells reduced E-cadherin and CADM1 levels. Functionally, knockdown of E-cadherin decreased spheroid cluster formation and knockdown of CADM1 decreased growth of BAP1-mutant uveal melanoma cells. Together, our findings demonstrate that BAP1 regulates the expression of CAMs which may regulate metastatic traits.
AB - BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene that is mutated in cancer, including uveal melanoma. Loss-of-function BAP1 mutations are associated with uveal melanoma metastasis and poor prognosis, but the mechanisms underlying these effects remain unclear. Upregulation of cell–cell adhesion proteins is involved with collective migration and metastatic seeding of cancer cells. Here, we show that BAP1 loss in uveal melanoma patient samples is associated with upregulated gene expression of multiple cell adhesion molecules (CAM), including E-cadherin (CDH1), cell adhesion molecule 1 (CADM1), and syndecan-2 (SDC2). Similar findings were observed in uveal melanoma cell lines and single-cell RNA-sequencing data from uveal melanoma patient samples. BAP1 reexpression in uveal melanoma cells reduced E-cadherin and CADM1 levels. Functionally, knockdown of E-cadherin decreased spheroid cluster formation and knockdown of CADM1 decreased growth of BAP1-mutant uveal melanoma cells. Together, our findings demonstrate that BAP1 regulates the expression of CAMs which may regulate metastatic traits.
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U2 - 10.1158/1541-7786.MCR-21-0657
DO - 10.1158/1541-7786.MCR-21-0657
M3 - Article
C2 - 35426938
AN - SCOPUS:85135575668
SN - 1541-7786
VL - 20
SP - 1260
EP - 1271
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 8
ER -