TY - JOUR
T1 - Combined Kdm6a and Trp53 Deficiency Drives the Development of Squamous Cell Skin Cancer in Mice
AU - Shea, Lauren K.
AU - Akhave, Neal S.
AU - Sutton, Leslie A.
AU - Compton, Leigh A.
AU - York, Conner
AU - Ramakrishnan, Sai Mukund
AU - Miller, Christopher
AU - Wartman, Lukas
AU - Chen, David
N1 - Funding Information:
This research is supported by the following grants from the National Institutes of Health: K08CA237727 (DYC), K08CA166229 (LDW), and R50CA211782 (CAM) as well as the Goldman Sachs Philanthropy Fund (LDW). We thank Dr. Timothy Ley for his indispensable advice and critical reading of this manuscript. Conceptualization: LDW; Formal Analysis: LKS, NSA, LAS, LAC, SMR, CAM, LDW, DYC; Investigation: LKS, NSA, LAS, CY, DYC; Supervision: LDW, DYC; Writing - Original Daft Preparation: LKS, DYC; Writing - Review and Editing: LKS, NSA, LAS, LAC, SMR, CAM, LDW, DYC.
Funding Information:
This research is supported by the following grants from the National Institutes of Health : K08CA237727 (DYC), K08CA166229 (LDW), and R50CA211782 (CAM) as well as the Goldman Sachs Philanthropy Fund (LDW). We thank Dr. Timothy Ley for his indispensable advice and critical reading of this manuscript.
Publisher Copyright:
© 2022 The Authors
PY - 2023/2
Y1 - 2023/2
N2 - Cutaneous squamous cell carcinoma (cSCC) has among the highest mutation burdens of all cancers, reflecting its pathogenic association with the mutagenic effects of UV light exposure. Although mutations in cancer-relevant genes such as TP53 and NOTCH1 are common in cSCC, they are also tolerated in normal skin and suggest that other events are required for transformation; it is not yet clear whether epigenetic regulators cooperate in the pathogenesis of cSCC. KDM6A encodes a histone H3K27me2/me3 demethylase that is frequently mutated in cSCC and other cancers. Previous sequencing studies indicate that roughly 7% of cSCC samples harbor KDM6A mutations, including frequent truncating mutations, suggesting a role for this gene as a tumor suppressor in cSCC. Mice with epidermal deficiency of both Kdm6a and Trp53 exhibited 100% penetrant, spontaneous cSCC development within a year, and exome sequencing of resulting tumors reveals recurrent mutations in Ncstn and Vcan. Four of 16 tumors exhibited deletions in large portions of chromosome 1 involving Ncstn, whereas another 25% of tumors harbored deletions in chromosome 19 involving Pten, implicating the loss of other tumor suppressors as cooperating events for combined KDM6A- and TRP53-dependent tumorigenesis. This study suggests that KDM6A acts as an important tumor suppressor for cSCC pathogenesis.
AB - Cutaneous squamous cell carcinoma (cSCC) has among the highest mutation burdens of all cancers, reflecting its pathogenic association with the mutagenic effects of UV light exposure. Although mutations in cancer-relevant genes such as TP53 and NOTCH1 are common in cSCC, they are also tolerated in normal skin and suggest that other events are required for transformation; it is not yet clear whether epigenetic regulators cooperate in the pathogenesis of cSCC. KDM6A encodes a histone H3K27me2/me3 demethylase that is frequently mutated in cSCC and other cancers. Previous sequencing studies indicate that roughly 7% of cSCC samples harbor KDM6A mutations, including frequent truncating mutations, suggesting a role for this gene as a tumor suppressor in cSCC. Mice with epidermal deficiency of both Kdm6a and Trp53 exhibited 100% penetrant, spontaneous cSCC development within a year, and exome sequencing of resulting tumors reveals recurrent mutations in Ncstn and Vcan. Four of 16 tumors exhibited deletions in large portions of chromosome 1 involving Ncstn, whereas another 25% of tumors harbored deletions in chromosome 19 involving Pten, implicating the loss of other tumor suppressors as cooperating events for combined KDM6A- and TRP53-dependent tumorigenesis. This study suggests that KDM6A acts as an important tumor suppressor for cSCC pathogenesis.
UR - http://www.scopus.com/inward/record.url?scp=85142699744&partnerID=8YFLogxK
U2 - 10.1016/j.jid.2022.08.037
DO - 10.1016/j.jid.2022.08.037
M3 - Article
C2 - 36055401
AN - SCOPUS:85142699744
SN - 0022-202X
VL - 143
SP - 232-241.e6
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 2
ER -