In this work, a signal transduction biosensor has been used as a novel electrical detection for identifying prostate specific antigen (PSA), a protein biomarker associated with prostate cancer. A direct nano-mechanical response of micro-fabricated self-sensing nanomechanical membrane (NMM) was used to detect the surface stress changes of antigen–antibody specific binding. The sensing principle is based on the surface stress changes induced by antigen–antibody interaction on the NMM surfaces. NMM consists of a membrane suspended by four piezoresistive sensing components. The isotropic surface stress on the membrane results in an uniaxial stress in each sensing component, which efficiently improves the sensitivity. After injecting the PSA target, as model biocontents, the piezoresistive responses were carefully analyzed and the feasibility of the piezoresistive membranes for biosensing were discussed in terms of device performance measures such as sensitivity, accuracy, and specificity. At the end, the results were compared with a standard cantilever.