  Finding cancer driver genes has been a focal theme of cancer research and
clinical studies. One of the recent approaches is based on network structural
controllability that focuses on finding a control scheme and driver genes that
can steer the cell from an arbitrary state to a designated state. While
theoretically sound, this approach is impractical for many reasons, e.g., the
control scheme is often not unique and half of the nodes may be driver genes
for the cell. We developed a novel approach that transcends structural
controllability. Instead of considering driver genes for one control scheme, we
considered control hub genes that reside in the middle of a control path of
every control scheme. Control hubs are the most vulnerable spots for
controlling the cell and exogenous stimuli on them may render the cell
uncontrollable. We adopted control hubs as cancer-keep genes (CKGs) and applied
them to a gene regulatory network of bladder cancer (BLCA). All the genes on
the cell cycle and p53 singling pathways in BLCA are CKGs, confirming the
importance of these genes and the two pathways in cancer. A smaller set of 35
sensitive CKGs (sCKGs) for BLCA was identified by removing network links. Six
sCKGs (RPS6KA3, FGFR3, N-cadherin (CDH2), EP300, caspase-1, and FN1) were
subjected to small-interferencing-RNA knockdown in four cell lines to validate
their effects on the proliferation or migration of cancer cells. Knocking down
RPS6KA3 in a mouse model of BLCA significantly inhibited the growth of tumor
xenografts in the mouse model. Combined, our results demonstrated the value of
CKGs as therapeutic targets for cancer therapy and the potential of CKGs as an
effective means for studying and characterizing cancer etiology.
