[8] Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest cancers. We investigated the role of KDM6A, a histone demethylase (an epigenetic eraser) that is frequently mutated in various cancers.

In this study, we discovered a surprising mechanism:

• Tumor Suppressor: KDM6A acts as a tumor suppressor in the pancreas.
• Super-Enhancer Activation: Its loss leads to the aberrant activation (“opening”) of super-enhancers that drive a squamous-like, aggressive identity.
• Therapeutic Vulnerability: Because this tumor subtype relies heavily on these super-enhancers (driven by BET proteins), these cancers are exceptionally sensitive to BET inhibitors (drugs that disrupt super-enhancers).

This work not only defined a specific molecular subtype of pancreatic cancer but also provided a direct therapeutic roadmap for targeting it—a prime example of “epigenetic therapy.”